She portrayed Susan Harper in the sitcom My Family (2000–2011), and appeared in the ITV dramas Agatha Christie's Poirot (2005–2013), Mr Selfridge (2015), and Girlfriends (2018).

The BBC series Who Do You Think You Are?, broadcast on 24 February 2009, revealed that her paternal grandfather Maurice Wanamaker (originally Manus Watmacher) was a tailor from Mykolaiv.

She appeared on stage playing the part of Beatrice opposite Simon Russell Beale as Benedick in the National Theatre's production of Much Ado About Nothing.

[11][12] In 1997, Wanamaker was the first person to speak on the stage of the newly completed replica theatre, Shakespeare's Globe, on London's South Bank.

[14] From May to October 2010, Wanamaker appeared in Arthur Miller's All My Sons as Kate Keller at the Apollo Theatre on Shaftesbury Avenue in London.

The work is a one-woman play that preceded Rattigan's Harlequinade, which she also appeared in, each night as part of a never-before-seen double bill.

[17] She returned to the Broadway stage in the 2023 Sharr White memory play Pictures From Home alongside Nathan Lane and Danny Burstein.

Starting in the early 1980s, Wanamaker began performing on screen, most notably in a number of critically acclaimed television productions, such as the BBC Television production Edge of Darkness; she was nominated for a BAFTA Award for her portrayal of the love interest of a suspected serial killer in the first instalment of the Granada series Prime Suspect.

She appeared with Wendy Hiller in The Countess Alice in 1992, playing a rebellious woman searching for the truth about her past in war-torn Germany.

She played Clarice, one of the dim-witted twin sisters of Lord Groan in Gormenghast (2000), a BBC television adaptation of Mervyn Peake's trilogy.

[27] In August 2014, Wanamaker 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.