Shortly after winning the Intercontinental title, Marella feuded with Chris Masters, narrowly retaining the title in his first defenses. On July 2, he dropped the title back to Umaga, after defeating him on June 24, at Vengeance: Night of Champions, by disqualification.
Marella then began a gradual heel turn and became increasingy jealous of his girlfriend, Maria. Over several weeks, they appeared together in a series of segments on Raw, including two "game show" skits, hosted by General Manager William Regal, which resulted in retired wrestler Ron Simmons winning a date with Maria, to Santino's dismay.
Marella began a publicity campaign against the WWE Films production, The Condemned, as its DVD release neared. He was eventually confronted by the film's star, Steve Austin, who argued the film's merits before delivering a Stone Cold Stunner to Marella and hosing him and Maria with beer. During the Austin angle, Marella repeatedly mocked him and his catchphrases in humorously broken English, starting a new comedic trend in his gimmick.
After a short angle with Jerry Lawler, Marella formed a tag team with Carlito.
Around this time, Maria was offered a photo shoot for Playboy magazine. After unsuccessfully persuading her to decline it, Marella tried to sabotage the cover unveiling (an in-ring segment of Raw), causing Maria to dump him. At WrestleMania XXIV, Maria had a "Playboy BunnyMania Lumberjack match". Santino interfered near the end of the match, pulling Maria off of a pin, and was punched by Jerry Lawler. After the match (which Maria's team lost), he was clotheslined by guest "Master of Ceremonies", Snoop Dogg. The next night, on Raw, Maria wrestled Marella. Seven other women ganged up on him, and held his legs apart for Maria to headbutt his testicles and pin him. This ended their feud.
Marella and Carlito then feuded with Hardcore Holly and Cody Rhodes over the World Tag Team Championship. During a title match between them, Roddy Piper distracted Marella, who was then pinned. This sparked a rivalry with Piper, which included a confrontation on Jimmy Kimmel Live!.
On the July 14, 2008 episode of Raw, Marella lost to Beth Phoenix, who had answered his open challenge. On the next episode, after he lost another open challenge to the returning D'Lo Brown, Marella and Phoenix kissed, both looking confused afterward. Over the next few weeks, they became a parody of a "power couple", soon called "Glamarella" (a portmanteau of Phoenix's nickname, "Glamazon", and "Marella". At SummerSlam, they wrestled Intercontinental champion Kofi Kingston and WWE Women's Champion Mickie James in a mixed-tag match with both titles on the line. Phoenix pinned James after hitting her finisher, the Glam Slam, giving Marella his second Intercontinental championship.
Marella then sought to become the "greatest Intercontinental champion of all time" by beating The Honky Tonk Man's record 64-week reign. Over the weeks, a "Honk-A-Meter" graphic informed viewers of his progress during his matches and segments. At Cyber Sunday, Marella was disqualified in a title match with The Honky Tonk Man (who fans voted for over other former champions Roddy Piper and Goldust). On the November 10 episode of Raw, after a reign of twelve weeks and one day, Marella lost the title to William Regal.
In January 2009, Marella entered the Royal Rumble, at #28. He was eliminated by Kane after (officially) 1.9 seconds, breaking The Warlord's 1989 record for shortest Royal Rumble appearance by a tenth of a second.
Marella's humour proved popular with audiences, and he turned face again before WrestleMania XXV, expressing his desire to be crowned the inaugural "Miss WrestleMania" in a 25-woman battle royale at the event. He challenged Mickie James to a match with one arm tied behind his back, with a battle royale spot on the line. He lost. The next week, in order to "prove" his eligibility, he revealed he was wearing a mankini. Instead, he was attacked by most of the female roster. Nevertheless, at WrestleMania, he won the battle royale, competing in drag as Santina Marella (Santino Marella's self-alleged twin sister), last eliminating Beth Phoenix and Melina.
Marella successfully defended the Miss Wrestlemania title against Phoenix at Backlash in three seconds, with help from The Great Khali. On the May 18 Raw, Marella lost the title to Vickie Guerrero, and won it back on June 7, at Extreme Rules, by defeating Vickie and Chavo Guerrero in a handicap hog pen match. On the June 22 Raw, Raw's new owner, Donald Trump, fired Santina and the Miss WrestleMania title was abandoned.
At WrestleMania XXVI, Santino Marella competed in the 26-man battle royale dark match, won by Yoshi Tatsu. He then tried to form a tag team with Vladimir Kozlov, who repeatedly refused the offer. On the May 31 Raw, Kozlov interfered in Marella's match, helping him win. On the July 19 Raw, they finally teamed to defeat William Regal and Zack Ryder. At Night of Champions 2010, Marella and Kozlov wrestled a Tag Team Turmoil match for the Unified Tag Team Championship, won by Cody Rhodes and Drew McIntyre.
On the October 11 Raw he defeated Zack Ryder to qualify for Team Raw at Bragging Rights, against Team SmackDown. He was the first of seven Team Raw members eliminated, pinned by Tyler Reks. On the October 25 Raw, after Sheamus had called him an "embarrassment" for being the first man out at Bragging Rights, Marella scored an upset victory over the former two–time WWE Champion. They wrestled twice more, both matches ending with John Morrison saving Santino from Sheamus' post-match assault.
On the November 15 Raw, Marella and Kozlov became number one contenders for the WWE Tag Team Championship by defeating The Usos. They unsuccessfully challenged The Nexus (Justin Gabriel and Heath Slater) for the title at Survivor Series. They won the Tag Team Championship in a four-way elimination tag match on the December 6 Raw, beating The Nexus, The Usos and Mark Henry and Yoshi Tatsu, after John Cena distracted Gabriel, allowing Marella to hit his Cobra finisher. After celebrating in the ring, Tamina kissed Santino, starting a relationship between them. She began accompanying Marella to his matches. Marella and Kozlov retained the Tag Team title at TLC: Tables, Ladders & Chairs, when Justin Gabriel and Heath Slater were disqualified after interference from Nexus member Michael McGillicutty. The next night on Raw, Marella and Snuka beat Ted DiBiase and Maryse in a mixed-tag match.
On January 30, 2011, Santino entered the Royal Rumble at number 37. He was one of the final two wrestlers, before being eliminated by Alberto Del Rio.
At Elimination Chamber, Marella and Kozlov lost the Tag Team title to Gabriel and Slater. At Wrestlemania XXVII, Marella teamed with Big Show, Kane, and Kofi Kingston (replacing the injured Kozlov) to defeat The Corre (Slater, Gabriel, Ezekiel Jackson and Wade Barrett) in an eight-man tag match. Marella's relationship with Snuka ended when she was drafted to SmackDown. On August 5, Vladimir Kozlov was released from WWE, ending the team.
Marella began teaming with Zack Ryder on the July 21 Superstars, beating Tag Team Champions David Otunga and Michael McGillicutty in a non-title match. On the August 1 Raw, Otunga and McGillicutty won the rematch.
Marella returned on the October 3 Raw, beating Jinder Mahal. On the October 31 episode, he pinned Jack Swagger with a roll-up pinfall after he spit water given to him by special guest, Beaker of The Muppets, in Swagger's face. The following Raw, Swagger defeated Marella by submission. On the January 6, 2012 episode of SmackDown, Marella defeated Drew McIntyre to become Smackdown General Manager Theodore Long's assistant. Marella teamed with Yoshi Tatsu on the January 27 SmackDown and "Hacksaw" Jim Duggan on the February 3 episode to face Tag Team Champions Primo and Epico, losing both times.
On the February 17 Smackdown, he won a battle royal to replace Randy Orton in the Elimination Chamber match at Elimination Chamber. He was eliminated last, by Daniel Bryan.
On the March 5 Raw, Marella defeated Jack Swagger for the United States Championship. On the next SmackDown, he successfully defended the title against Swagger in a steel cage match, by escaping through the cage door. At WrestleMania XXVIII, Marella was the team captain of Team Teddy, which lost to Team Johnny, after interference from Eve. The next night on Raw, he successfully defended the title against Swagger and Dolph Ziggler in a Triple Threat Match. On the April 16 Raw, Marella successfully defended against David Otunga. On the Extreme Rules pre-show, Marella retained the title from The Miz. The next night on Raw, Marella unsuccessfully tried to earn a WWE Championship match at Over the Limit in a Beat the Clock Challenge against The Miz.
Marella then reunited with Zack Ryder, facing teams including Primo and Epico, Curt Hawkins and Tyler Reks and Titus O'Neil and Darren Young.
Marella then feuded with Alberto Del Rio's ring announcer Ricardo Rodriguez, leading to a non-title Tuxedo match at No Way Out, which Marella won.
On the June 25 Raw, Marella successfully defended the United States Championship against Jack Swagger. Four days later on SmackDown, he and Intercontinental Champion Christian defeated David Otunga and Cody Rhodes to qualify for the World Heavyweight Championship Money in the Bank ladder match at Money in the Bank, which was won by Dolph Ziggler.
On the July 27 and August 3 episodes of SmackDown, Marella lost to Antonio Cesaro in non-title matches. On August 19, on the SummerSlam pre-show, Marella lost the United States Championship to Cesaro. Marella lost his rematch on the September 3 episode of Raw. On the September 21 SmackDown, he defeated Cesaro in a non-title match to earn another title shot. The next week on SmackDown, Marella lost again.
On October 3, on the inaugural WWE Main Event, Marella and Zack Ryder entered a Tag Team Championship tournament, and defeated International Airstrike (Justin Gabriel and Tyson Kidd) in the quarterfinals. The next week on Raw, they were eliminated in the semifinals by Rhodes Scholars (Cody Rhodes and Damien Sandow). On the December 24 Raw, Marella teamed with Brodus Clay, International Airstrike and The Usos to defeat 3MB, The Prime Time Players and Tensai. On the December 28th edition of SmackDown! Marella was randomly selected to face Big Show for the World Heavyweight championship. He was later injured (in kayfabe) while attempting to do a brogue kick while training with Sheamus. In the middle of January, Speaking through his official Twitter account, Marella noted that he was back working out at the gym. Santino had been dealing with a neck injury and noted that after a recent MRI, the results weren’t looking good. Despite this, Santino recovered and took part at the Royal Rumble as number 5 but he was the first eliminated. After a two-month absence, Marella returned to Raw on April 1, losing to Mark Henry.
After another five month hiatus, he returned on September 9, and defeated Antonio Cesaro. On the next episode of SmackDown, he defeated Damien Sandow with the cobra. He defeated Heath Slater on the next episode of Smackdown and began to align himself with The Great Khali and Hornswoggle. Marella then began a feud with Cesaro and his tag team partner Jack Swagger. Santino defeated Swagger on the 20th September episode of Smackdown and he defeated Cesaro on the 30th September episode of Raw in singles competition. On October 6 at WWE Battleground, Marella and The Great Khali were defeated by Cesaro and Swagger in a tag team match. They were defeated again by the Real Americans on the following episode of Raw but after the match Santino gained revenge by attacking Cesaro with the cobra. On the 21th October episode of Raw, he defeated Heath Slater, dressed as Elvis Presley. After the match, he danced with Jerry Lawler on the announce table. On the 30th October episode of Main Event, he defeated again Heath Slater in singles competition. On November 11, Santino teamed with Los Matadores to defeat 3MB (who were working as "The Union Jacks"). After that, he took a brief hiatus once again.
On February 3, 2014, Marella returned to television and invited Emma into the ring from the crowd to have a "dance-off" with Summer Rae, starting a feud with her and Fandango. Emma would go on to win the dance competition against Summer Rae on the February 21st edition of Smackdown. Santino participated in the Andre The Giant Memorial Battle Royal at WrestleMania XXX, eliminating The Miz, before being eliminated by Alberto Del Rio. On May 5, 2014, Santino participated in a 20-man battle royal for Dean Ambrose's WWE United States Championship, but he was eliminated by Rybaxel's members.
Santino officially announced his retirement from in-ring competition at a WWE live event in Toronto, Ontario on July 6, 2014, after sustaining a third neck injury. He said that though his in-ring career is over, he still looks to entertain the fans while working for WWE.
Marella returned on the November 24 episode of Raw to promote his new movie, Jingle All the Way 2 with co-star Larry the Cable Guy. Marella served as the Guest General Manager for the December 5 episode of SmackDown, as well as to present a Slammy Award on Raw dated 8 December. Sometime in early 2015, Marella left the company. He made a return to WWE television on a December 21, 2015 edition of Monday Night Raw to present an award at the Slammy Awards. The next night, on SuperSmackDown, Marella became angry when Stardust and The Ascension ruined his Christmas Party and vowed revenge, receiving the help of Neville and Titus O'Neil.
On May 6, Marella was released from WWE along with 7 other superstars.