Mangan played the narcissistic Guy Secretan in the BAFTA-winning British sitcom Green Wing. In Channel 4's The World's Greatest Comedy Characters, Guy was voted 34th. He starred as Keith in Never Better, a British television sitcom on BBC Two. He plays a recovering alcoholic Keith Merchant and Kate Ashfield is his long-suffering wife Anita. The series was written by Fintan Ryan for World Productions.

After graduating from RADA in 1994, Mangan did not pursue lead roles on-screen, preferring to take what he saw as the less limited opportunities on the stage. Between 1994 and 2000, he performed in plays by Shakespeare, Shaw, Coward, Benn and Goldsmith (among others) throughout the UK and the West End before joining the theatre company Cheek by Jowl for an international tour of Much Ado About Nothing, earning him a nomination for a National Theatre Ian Charleson Award. He worked again for Director Declan Donnellan at the Royal Shakespeare Company in School for Scandal, and at the Savoy Theatre in Hay Fever.

Mangan's breakthrough television performance was as Adrian Mole in the six-part BBC TV show series Adrian Mole: The Cappuccino Years in 2001. That same year he appeared in Sword of Honour on Channel 4, alongside Daniel Craig.

He appeared opposite Keira Knightley in the 2002 short New Year's Eve, and played the leading role in SuperTex (2003), a Dutch film, filmed in English and directed by Jan Schütte. He played a Comedian in Festival is a 2005 British black comedy about a number of people at the Edinburgh Festival Fringe directed by Annie Griffin. The general shots of the festival were filmed during the 2004 event. Mangan was nominated for a Scottish BAFTA for his performance.

Confetti, a 2006 British mockumentary romantic comedy film, was released on 5 May 2006. It was conceived and directed by Debbie Isitt and stars many British comedians, including Jessica Stevenson, Jimmy Carr, Martin Freeman, Mark Heap, Julia Davis, Robert Webb, and Olivia Colman. It follows a bridal magazine competition for the most original wedding, the ultimate prize being a house, and the three couples who are chosen to compete. Mangan plays one of the grooms, a professional tennis player. The film follows the contestants in a fly-on-the-wall documentary style, akin to The Office. The script was entirely improvised.

In 2008 he played the title role in The Norman Conquests, directed by Matthew Warchus, at The Old Vic and then at the Circle in the Square on Broadway. The production was a huge critical success earning several Tony Award nominations, including one for Mangan himself and won the Tony Award for Best Revival.

In 2009, Free Agents, a romantic black comedy starred Mangan, Sharon Horgan and Anthony Head. Originally a pilot for Channel 4 in November 2007, the series began on 13 February 2009. It spawned a short lived US remake, which was cancelled after just 4 episodes aired, although 4 more were later released on Hulu.

He starred in Beyond the Pole, a 2010 British mockumentary adapted from the cult BBC radio series of the same name. It received its UK cinema release in 2010. Directed and produced by David L. Williams

He appeared in Episodes, a British/American television comedy series created by David Crane and Jeffrey Klarik and produced by Hat Trick Productions. It premiered on Showtime in the United States on 9 January 2011 at 9:30 pm and on BBC Two in the UK on 10 January 2011.

In 2012 he appeared at the Royal Court (for the second time) in a Joe Penhall play, Birthday, directed by Roger Michell, playing a pregnant man.

In 2014, Mangan voiced the title role in Postman Pat: The Movie, a British 3D computer-animated comedy film featuring Postman Pat, star of a long-running BBC children's series. It was originally due to be released on 24 May 2013, but was pushed back to a year later. Pat's singing voice was performed by Ronan Keating. Other voice actors in the film included Jim Broadbent, Rupert Grint, and David Tennant.

In August 2014, Mangan was one of 200 public figures who were signatories to a letter to The Guardian expressing their hope that Scotland would vote to remain part of the United Kingdom in September's referendum on that issue.

In 2018 Stephen Mangan played the lead role in a comedy British TV Series Bliss that was aired on Sky One.