Silent Witness was created by Nigel McCrery, a former murder squad detective based in Nottingham, and the original lead character was based on Professor Helen Whitwell, a real forensic pathologist based in Sheffield whom McCrery had known while serving as a police officer.

The show's setting has changed over the years: the first three series were set in Cambridge, it moved to London from series 4, then to the Lyell Centre (UCL's Pathology Department) from series 6, and eventually to a new centre in Birmingham from series 29 following a 2023 production move.

Harry Cunningham's departure at the end of series 15 was never actually shown on screen because the decision to have him leave was made after filming had already been completed, and the episode order was rearranged so that 'And Then I Fell in Love' aired last despite being originally scheduled second.

The series has featured guest appearances by numerous actors who later became major stars, including Emily Mortimer, Idris Elba, Nicholas Hoult, Benedict Cumberbatch, Jodie Comer, Daisy Ridley, and Daniel Kaluuya.

The theme music used from series 2 onwards, titled 'Silencium', is performed by John Harle with vocals by Sarah Leonard; its full chamber orchestra and soprano saxophone arrangement was first publicly performed at the Canterbury Festival on 22 October 2011.

The series 15 episode 'Redhill', written by Ed Whitmore and first broadcast in April 2012, received 632 complaints over a sadistic sexual and murderous attack scene, leading the BBC Trust's editorial committee to censure the BBC for breaching harm and offence guidelines.

In 1998, writer John Milne won an Edgar Award from the Mystery Writers of America for the second series episode 'Blood, Sweat and Tears'.

Series creator Nigel McCrery wrote four tie-in novels during the show's early years following characters Sam Ryan, Trevor Stewart, Superintendent Tom Adams, and a new character DS Stanley Sharman, with a planned fifth novel, 'In Search of Evil', ultimately cancelled before its 2003 release.