From 2000-2002, O'Brien was a key panelist on Five's The Wright Stuff.
In early 2001, O'Brien presented A Knight With O'Brien, a talk show on Anglia Television.
With his wife, Lucy O'Brien, he fronted Channel 5's 2001 general election talk show 5 Talk, securing a review from Clive James, who wrote: "James, in particular, is a pink-shirted walking encyclopedia of political savvy". Recently, O'Brien and wife Lucy have occasional weekend and Bank Holiday phone-ins for LBC.
Other regular appearances include: Sky News, The Big Questions (BBC 1), The Alan Titchmarsh Show (ITV).
O'Brien first appeared on LBC during 2002 as a holiday cover presenter, gaining his own weekly programme in January 2003 and becoming a full-time presenter in 2004. Regular features of his show include the "Mystery Hour", in which listeners phone in with various things that puzzle them and other callers attempt to give a solution.
O'Brien made national headlines in April 2009 when footballer Frank Lampard phoned his show to object strenuously to tabloid stories about his private life and O'Brien's discussion of them. Lampard's former fiancée, Elen Rivas, had alleged that Frank Lampard had turned their home into a bachelor pad while she and Lampard's children were living in a rented flat. Lampard phoned in, objecting to the assertion that he was "weak" and "scum" for allowing his children to live in inferior conditions to him, and to say that he had fought "tooth and nail" to keep his family together. Public comments on Lampard's reaction praised Lampard’s "brave" and "articulate" handling of the situation. The exchange later earned O'Brien, who defended his conduct in an equally heated exchange with Kay Burley on Sky News, a Bronze Award in the Best Interview category of the 2010 Sony Radio Academy Awards.