She came to prominence in the BBC hidden-camera show 3 Non-Blondes, having also appeared in other television series such as The Fast Show and The Bill. In 2006 she wrote and starred in her own comedy sketch show called Little Miss Jocelyn, a second series of which aired in January 2008. This show marks the first time in the history of television – in either the US or the UK – that a black woman has been given her own solo comedy sketch show.
In 2000, Esien won the Best Newcomer award at the Black International Comedy Awards, and she won a New Talent Award in the Women in Film and Television Awards 2006.
In 2007, Esien featured in Girls Aloud and Sugababes' Comic Relief video for "Walk This Way", where she puts a parking ticket on Ewen Macintosh, a reference to the character Jiffy from the show Little Miss Jocelyn.
Esien appeared in the second series of The Sarah Jane Adventures as Clyde Langer's mother, Carla. In 2010, Esien reprised the role in two further episodes of the show, titled The Empty Planet which aired on 1 and 2 November 2010, as well as in the fifth series story, The Curse of Clyde Langer which aired on 10 and 11 October 2011.
On 11 June 2009, it was stated that Little Miss Jocelyn would not be brought back for a third series. In November 2009, Esien played the part of waitress Cindie Smith in the ITV series Collision.
On 22 September 2010, Esien returned to BBC Three for One Non-Blonde: Down Under, an 8-part comedy stunt show with new character creations. She plays characters such as a hermaphrodite rapper and a socialite, touring New Zealand. She also appeared alongside famous British comedians in BBC One's Ronnie Corbett Christmas special, The One Ronnie.
In 2011, Esien appeared as Tasha in British comedy Anuvahood. and also in British comedy show Some Girls.
In January and February 2013, she appeared in One Monkey Don't Stop No Show by the American playwright Don Evans, at the Tricycle Theatre, London; a UK premiere for the play, and thereafter toured with the play nationally.
In 2013, she appeared in Gangsta Granny as Kelly.
Esien's other TV appearances include Autumn Leaves, a BBC comedy-drama; Some Girls, Uncle Max, After You've Gone, Holby City, The Lenny Henry Show, Ed Stone Is Dead, Comedy Nation, The Fast Show, Douglas, The Bill and In The Name of Love (TV movie). She has also made numerous stage appearances.
She appeared in the 2010 film StreetDance 3D and wrote an episode of the American reality TV show Jon & Kate Plus 8.[