Fatone met his wife, Kelly Baldwin, whilst they were still in high school in 1993. After joining Nsync two years later, their relationship was off-and-on.

It was a much speculated rumor that Fatone had briefly dated singer Pink in early 2000, to which Pink stated, “[Joey] took me to Friendly’s as a casual date, not like a date-date. I just wanted ice cream. We were in the friend zone.” The singer has stated that although they did technically go on a date, it was more platonic and that Fatone was “a total sweetheart.”

In the summer of 1995, after befriending Chris Kirkpatrick, a fellow Universal Studios stage performer who was singing in a doo-wop group, he became the fourth member of NSYNC, along with Justin Timberlake and JC Chasez. Then Lance Bass was added to the group that would become NSYNC. In 2001, Fatone co-starred with *NSYNC bandmate Lance Bass in the Miramax film On the Line, he guest starred with NSYNC on a 2001 episode of The Simpsons episode New Kids on the Blecch, and also did voice work with Bass on the same episodes of Disney’s Kim Possible and Adult Swim’s Robot Chicken.

Fatone co-starred in the 2002 dramatic comedy motion picture My Big Fat Greek Wedding as Toula’s cousin Angelo, appeared in the show My Big Fat Greek Life, and reprised the role again in the 2016 sequel My Big Fat Greek Wedding 2. He acted in the critically acclaimed movie The Cooler. He has had minor roles in both the experimental film Red Riding Hood and Homie Spumoni, the latter alongside Jamie-Lynn Sigler. Fatone has also been on Broadway, performing leads in Rent in 2002 and in a revival of Little Shop Of Horrors.

On September 9, 2004, Fatone married his high school sweetheart, Kelly Baldwin, at Oheka Castle on Long Island, New York, in a ceremony that was attended by all his Nsync bandmates. Fatone and his wife have two daughters: Briahna Joely, born March 21, 2001, and another born January 2010. Fatone’s best friend, Lance Bass, is their godfather.

In 2005, NBC contracted Fatone as the host (or “ringmaster”) of its celebrity reality series Celebrity Circus. That year, he also guest starred in the Hannah Montana episode “Bye Bye Ball” as restaurant owner Joey Vitolo, a former baseball player who forces Hannah to sing in exchange for a replacement signed ball for her brother. Fatone went on to depict another baseball player on the Disney Channel series Imagination Movers in 2010. From July 6–18 of that same year, he also performed in the musical “The Producers” at the Pittsburgh Benedum Center in the role of comedic Nazi Soldier Franz Liebkind.

Fatone hosted NBC’s The Singing Bee as well as the Australian version of the show on Nine Network. On August 21, 2007, it was announced that he, along with Lisa Rinna, would replace Joan Rivers and Melissa Rivers as hosts of TV Guide’s red carpet pre-shows for the 2007–2008 season. His hosting duties with TV Guide continued for the 2008–2009 season.

On February 1, 2007, the ABC television network announced that Fatone would participate in season 4 of the American version of Dancing with the Stars, which debuted March 19, 2007. He ended up placing second, losing the mirror ball to Apolo Anton Ohno and Julianne Hough. He competed with professional partner Kym Johnson. Fatone participated in the 15th season of Dancing with the Stars for a second chance to win a mirror ball trophy, again dancing with Kym Johnson. They were the second couple eliminated. He later returned in season 27 during Trio Week as a trio partner to John Schneider and Emma Slater.

On October 18, 2009, Fatone attended the TNA Wrestling’s biggest annual pay-per-view event TNA Bound for Glory and co-hosted the live pre-show alongside Jeremy Borash. This was not the first time Fatone has been linked to TNA, as he has been spotted at Universal Orlando where TNA tapes its weekly television program.

Fatone has lent his voice to several episodes of Robot Chicken, starring as himself in a kung fu skit called “Enter the Fat One” and having a vocal cameo in the show’s Star Wars episode. From 2010 to 2015, Fatone served as the announcer for host Steve Harvey on the show Family Feud. In 2011, he took a job hosting the Live Well Network series My Family Recipe Rocks. In October of the same year, he also appeared in the horror film Inkubus.

In January 2012, he was one of eight celebrities participating in the Food Network reality series Rachael vs. Guy: Celebrity Cook-Off. Though eliminated in week six, he secured a $5,000 award for his charity, the Fatone Family Foundation.

In February 2013, Fatone appeared on Holland America Line’s “Dancing with the Stars at Sea,” aboard the MS Eurodam. He returned to Dancing with the Stars at Sea on Holland America Line’s MS Nieuw Amsterdam in January 2014, alongside co-star . He was paired with Lacey Schwimmer and appeared alongside Mark Ballas, Sabrina Bryan, and a dance ensemble. Unlike the TV show, however, this was not a competition and there were no eliminations.

On August 25, 2013, the members of NSYNC regrouped for a one-off performance at the 2013 MTV Video Music Awards. They performed a medley of “Girlfriend” and “Bye Bye Bye.” After the performance, Lance Bass said that the group does not have plans at the moment for a reunion tour or new music.

Fatone made a cameo in February 2014 on the hidden camera show Impractical Jokers, standing in for one of the show’s stars, Brian Quinn, during a challenge. He later appeared as a guest in a 2017 episode, having given permission to film at his Orlando-based hot dog restaurant Fat One’s. Since 2016, he has been the host or featured guest in specials such as “Nitro Circus Spectacular”, “The Joker Games”, and “Fantasy Draft”. He has served as the permanent host of the spin-off series Impractical Jokers: After Party since its premiere in 2017. His relationship with the show’s stars also earned him a cameo in the 2020 film Impractical Jokers: The Movie.

In April 2014, Fatone began hosting the Food Network cooking competition Rewrapped, where chefs must recreate classic snack foods and then create new dishes using said snack food. In August of the same year, Fatone became the host of another series, Parents Just Don’t Understand, which aired on the Hub Network prior to its rebranding as Discovery Family. He also guest starred in three episodes of The Jack and Triumph Show in 2015.

In 2019, Fatone portrayed the Rabbit on season one of the singing competition show The Masked Singer, tying with Rumer Willis for fourth place overall. He currently serves as the presenter of Common Knowledge, a game show that premiered on January 14, 2019 on the Game Show Network.