Brand's first significant stand-up appearance was at the Hackney Empire New Act of the Year final in 2000. Although he did not finish in the top three, his performance attracted the attention of an agent, John Noel. His first big tour was his show Shame which he toured the UK and performed to sell out audiences drawing on embarrassing things that have happened and the tabloid press and how they have treated him since he became famous. In late November 2006 Russell put on a secret stand-up show for anyone who had added him as a friend on MySpace. This show featured unseen material not featured on his DVD. Brand performed a sketch with close friends Matt Lucas & David Walliams for a Little Britain live show for Comic Relief in which he played a crossdressing plumber who comes out to "fellow crossdresser", Emily Howard. Brand appeared in a sketch and did stand-up at the 2006 Secret Policeman's Ball. In March 2007, Brand performed a charity show with Noel Fielding centered on the Goth Detectives. The idea for the show was inspired by Jonathan Ross, who, on The Big Fat Quiz of the Year 2006, suggested that Fielding could play Bob Skeleton ("Indie Detective"), which led to Brand and Fielding jokingly describing a fictional scenario in which they were "Goth Detectives."

Brand's first presenting role came as a VJ on music channel MTV presenting Dance Floor Chart and MTV Select. However he was fired after coming to work dressed as Osama bin Laden the day after 9/11.

After MTV, Brand featured in RE:Brand. The show was a British documentary and comedy television program that aimed to take a challenging look at cultural taboos. It was conceived, written and hosted by Brand, with the help of his comic partner for many projects, Matt Morgan. The series was shown on the now defunct digital satellite channel UK Play in 2002. As confirmed in his memoirs 'My Booky Wook' and mentioned in his radio shows, Brand was often drunk or on heroin during the filming of RE:Brand.

In 2004, he hosted Big Brother's Eforum on E4, a sister show to Big Brother 5. The show gave celebrity guests and the public the chance to have their say on the goings-on inside the Big Brother house. Brand hosted a one-off special called Big Brother According to Russell Brand in which Brand takes a surreal, sideways look at Big Brother through the ages.

Brand worked for MTV once again in spring 2006 when he began presenting the chat show 1 Leicester Square. Guests have included Tom Cruise, Uma Thurman McFly and Boy George. On November 9, 2006 it was announced that Brand would host his own chat show called The Russell Brand Show. The first episode was broadcast on Friday November 24 on Channel 4 and the show ran for five weeks.

Brand hosted the 2007 BRIT Awards and presented Oasis with their Outstanding Contribution to Music award at the event. He also hosted one hour of Comic Relief. Brand returned to Channel 4 to host Russell Brand's Ponderland, in which he discusses various topics like childhood and science through stand-up comedy.

Brand's first major TV acting work was an appearance in an episode of The Bill in 1994. In 2002, he filmed roles in the television comedy dramas, Cruise of the Gods and White Teeth. In 2005 he played Tommy in the BBC sitcom Blessed which was written and directed by Ben Elton.

In 2007, Brand played a recovering crack addict called "Terry," in the pilot for ITV comedy The Abbey, written by Morwenna Banks. Brand first major film role was in the 2007 film St Trinian's, in which he played Flash Harry, although it is not known if he will reprise the role for the upcoming sequel St Trinian's: The Legend of Fritton's Gold. He filmed a small role in 2006 for Penelope. His breakthrough role was in the 2008 film Forgetting Sarah Marshall, in which he played Aldous Snow, the boyfriend of the title character (played by Kristen Bell. Brand received rave reviews for his performance as Snow. He will again play the character of Aldous Snow for a buddy comedy entitled Get Him to the Greek, co-starring Jonah Hill