Mafham began his career at The Royal Shakespeare Company in 1990. He was with the RSC for four years.

Mafham first came to prominence when he played Nigel Hawthorne’s emotionally damaged son Daniel Pascoe in Paula Milne’s The Fragile Heart. The drama was screened on Channel 4 in the UK in 1996. It won the 1997 BAFTA award for Nigel Hawthorne as Best Actor, and was nominated for several awards including Best Drama Serial. It was also nominated in the Royal Television Society awards that year.

Mafham played Mortimer Lightwood in the BBC’s 1998 adaptation of Charles Dickens’ Our Mutual Friend. Much of the story is seen from Mortimer’s perspective. Our Mutual Friend was acclaimed worldwide, and won four BAFTAs including Best Serial. It was nominated for four more BAFTAs, as well as awards from the Royal Television Society, the Broadcasting Press Guild and the San Francisco International Film Festival. In 1999 he played Grahame Tranter in the Midsomer Murders episode “Death of a Stranger.”

In February 2010, Mafham guest-presented The Afternoon Show, RTÉ television’s flagship daytime show.

From February 2011 Mafham played Osborne, to critical acclaim, in the 2011 National Tour of David Grindley’s award-winning production of RC Sherriff’s Journey’s End. The production transferred to the Duke of York’s Theatre in the West End in July 2011.

In October 2011 Mafham took part in the new Bush Theatre’s inaugural event Sixty-Six Books, in a two-handed play by Jack Thorne based on the Book of Daniel. The play’s title was James Oliver and he starred opposite Miranda Raison.

On 6 June 2014 Mafham took part in the BBC Radio 2 D Day 70th-anniversary concert at the Royal Albert Hall. The concert was broadcast live on Radio 2 and at over 150 cinemas across the UK. The event was presented by Dermot O’Leary, Jeremy Vine and Louise Minchin. Sir Patrick Stewart read Churchill.

Mafham appeared in the play Linda, written by Penelope Skinner and directed by Michael Longhurst, which opened on 26 November 2015 at the Royal Court Theatre in London. He played Neil, the husband of Linda, played by Noma Dumezweni who replaced Kim Cattrall after she left the production in the final week of rehearsals, citing “doctor’s orders”.

In spring 2015 Mafham played Antonio in The Merchant of Venice at Shakespeare’s Globe Theatre. Jonathan Pryce played Shylock. The production was revived for a major tour in 2016, visiting New York, Washington and Chicago in the U.S. and several cities in China before returning to Shakespeare’s Globe in October and culminating in a run in Venice at the Teatro Goldoni. The production received rave reviews.

His more recent feature films include playing Dr Wangel in Heart of Lightness, a film directed by Jan Vardøen set in Arctic Norway based on Henrik Ibsen’s play The Lady From The Sea. He played Sir Horsa in Dragonheart, Druid’s Curse, the third in Universal Studios’ Dragonheart series, directed by Colin Teague; and Guy ‘Bullet Face’ Bidwell in Sniper: Legacy, a Sony Pictures film with Tom Berenger and Dennis Haysbert, directed by Don Michael Paul. Mafham returned as Bidwell in the next instalment of the Sniper film series released in 2016.

In February 2016 he appeared in the BBC TV series Father Brown as Sir Malcolm Braithwaite in episode 4.6, “The Rod of Asclepius”.

In autumn 2017 Mafham appeared in King Lear (as Albany), at the Chichester Festival Theatre. Ian McKellen played Lear and featured Sinéad Cusack as a female Kent. The production received rave reviews, and Mafham’s performance described as “revelatory” in the Daily Mail. The production transferred to the West End in 2018.