Merchant began performing stand-up comedy in the late 1990s to critical success, though he decided to focus more on his work with writing partner Ricky Gervais after the success of The Office. Merchant returned to stand-up with a nationwide tour of the United Kingdom in September 2011, under the title Hello Ladies. The tour, which ended in New York, was later released on DVD. In late 2012, the tour continued in Australia and New Zealand. Merchant performed his first-ever stand-up tour of Scandinavia in October 2014, performing in 11 different cities as part of a European festival circuit. In an interview with Marc Maron, Merchant listed Eddie Izzard, Stewart Lee, Ross Noble and Jimmy Carr as stand up comedians he admires and John Cleese as his main comedic influence.
In January 2011, Merchant appeared alongside many other comedians at the 'Free Fringe Benefit' at the Bloomsbury Theatre, London, in a show of stand-up to benefit the Free Fringe at the Edinburgh Comedy Festival.
Merchant is the voice of Wheatley in Valve's 2011 video game Portal 2, a role which earned him widespread acclaim among reviewers. He has stated that the project was "exhausting", he is also "very pleased by the response people have had to it. What I was really pleased by how people seemed to respond to it in the way they do with a movie they've enjoyed, or a TV show they've enjoyed." In 2013, he reprised this role as the voice of the Ap-Sap in Team Fortress 2, a weapon based on the Wheatley core.