Cullen was born in Peterborough, Ontario. Cullen rose to fame in 1987 as a member of the musical comedy trio, Corky and the Juice Pigs. Corky and the Juice Pigs toured all across the world, winning awards at places like Edinburgh Fringe and for performing at Just for Laughs in Montreal eight times. The group also appeared on Fox's own MADtv. They made two comedy albums. The group officially broke up in 1998, after ten years of performing together.
After there breakup, Cullen started to perform alone, sometimes with musician Dylan Goodhue. He wrote and created his own one-man show called Wood, Cheese and Children which moved on and became a special in CTV's Comedy Now! series. The series was nominated for a Gemini Award. In 1998, he performed in a sketch comedy show in England called Unnatural Acts.
Cullen often appeared on Canadian televison, such as CBC's Royal Canadian Air Farce, CTV's The Associates, and The Comedy Network's own Patti and Liocracy. He also made appearances on American sitcoms, including The Ellen Show and Payne. He has appeared as a guest on The Late Show with Craig Kilborn, he was the host of NBC's Late Friday, and has been shown in comedy skits on The Tonight Show with Jay Leno in which he visited an event and interviewed people attending the event. He also voiced Four, Five, and Seven on Seven Little Monsters. He has made appearances on Comedy Central's Premium Blend, and his own Comedy Central Presents in 2002. He portrayed comedian Jackie Gleason in the 2002 TV-movie Martin and Lewis.
In 2003, Cullen created his very own sitcom, The Seán Cullen Show, for CBC. It lasted one season with six episodes. At Christmas time in 2003, CBC aired a Christmas special called Seán Cullen's Home for Christmas special. In 2002 and 2003 Cullen was the host of the 17th and 18th Annual Gemini Awards Galas, and one year after being the host he won a Gemini Award for hosting the former gala. He won awards in 2001 for his performance at Just for Laughs, and in 2006 for being the host of What Were They Thinking, a CTV program in which Cullen visited many weird and somewhat unable to be explained Canadian landmarks. Cullen, also with Goodhue, where the hosts of the The Just For Laughs 20th Anniversary Special which aired on CBC.
In 2004, Cullen made an appearance as Max Bialystock in the Canadian version of The Producers for Mirvish Productions, which gave him a nomination for a Dora Mavor Award. In July 2005, CBC Radio One started airing Simply Seán, a music and radio program hosted by himself.
In the 2010 and 2011 seasons of the Stratford Festival, Cullen protrayed Smee in Peter Pan, Pseudolus, in A Funny Thing Happened on the Way to the Forum, and Vinnie in The King of Thieves by George F. Walker.
Cullen has a long relationship with the band members of Barenaked Ladies, the band was created, with its original members, opened for Corky and the Juice Pigs on an early all around Canada tour in 1989. On the Barenaked Ladies' American and Canadian holiday tour, Cullen went with the band on the road. He would tell a funny version of the nativity story, and sing Christmas carols with band member Kevin Hearn.
He voices Lucius Heinous VII, on the Teletoon show Jimmy-Two Shoes, Principal General Barrage on Detentionare, Piggy and Narwhal on Almost Naked Animal, Gus, Deep Space Dave, and Nefarious on Rocket Monkeys.
His first chance at becoming a stand-up comedian was outside of Toronto, Ontario at a college lunchtime gig. His performance was supposed to be one hour but it ended up lasting for fifteen minutes. He was inspired by Eddie Izzard because of his great way of improvisation, and Monty Python because of his way of being ridiculous, and for his Second City's parodies. He also admires intelligent people like Pathon Oswald, and Elen and Andy Kindler as his stand-up comedy heroes because they are not scared of looking dumb as they try to entertain the audience. Cullen enjoys watching television shows such as, WKRP, Saturday Night Live, Monty Python, Cheers Arrested Development, The Larry Sanders Show, and The Colbert Report. For his favorite movies he enjoys Bladerunner, Shaun of the Dead, Life of Brian, Lord of the Rings, Aliens, It's a Wonderful Life, A Christmas Carol, and many James Bond movies.
Cullen is also known for being one of the finalists on the Last Comic Standing, a reality talent show that airs on NBC which searches for the most hilarious and craziest stand-up comedian all around the country. The winner of the show will get a contract with NBC Universal and a Bravo Special.
Cullen is connected with Balzac's Coffee, a chain of cafés located in Southern Ontario. The company often sponsors Cullen's events, including his own comedy show, The Sean Schau!. Cullen appears in other videos which promote the chain, which are shown on his Myspace page, and YouTube.
In 2012 he became a regular panelist on the Canadian version of Match Game, which airs on The Comedy Network.