Mafham first came to prominence when he played Nigel Hawthorne's emotionally damaged son Daniel Pascoe in Paula Milne's The Fragile Heart.

Mafham played the central character—a high-tech assassin in the Swiss Alps stricken with a conscience—in Duncan Jones's first film Whistle.

[4] 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.

Since then, Mafham has appeared in more than 70 productions, including the films The English Patient and Shooting Fish, and regular character Andrew Argyle in two seasons of the ITV medical drama Always and Everyone (A&E).

His more recent television appearances includes the opening episode of the second series of the BBC drama The Musketeers, playing General De Foix; an episode of the BBC series New Tricks, playing a Tory minister suspected of murder; and Humans on Channel 4 and AMC, as recurring character Chief Superintendent Shaw.

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

Mafham appeared as Jerry Waldegrave, a guest lead, in the new HBO/BBC television series Strike based on J. K. Rowling's detective novels.

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 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[15] and culminating in a run in Venice at the Teatro Goldoni.

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.

[23] In September 2023 Mafham appeared in the first major revival of the Polly Stenham play That Face at the Orange Tree theatre, Richmond, London.

He played Ethan Frome in the BBC Radio 4 adaptation of Edith Wharton's novel of the same name; Hugh Cazalet in the mammoth serialisation of Elizabeth Jane Howard's wartime saga The Cazalets; the Duke of Buckingham in the dramatisations of The Stuarts, and most recently Geoffrey Marshall, a factory owner in Tyneside, in the Radio 4 series Home Front.

[26] Mafham appeared in the Big Finish audio Companion Chronicle adventure The Jigsaw War which was a two hander with Frazer Hines.

[27] He featured in the fourth Doctor adventures with Tom Baker, The Dalek Contract and The Final Phase, released in June and July 2013.