Johnson's first professional acting role came in the play Four Seasons at the 1985 Edinburgh Festival Fringe. For the rest of the 1980s he made minor appearances in television series such as Casualty and London's Burning, before playing detective Stevie Johnson in the London Weekend Television series Anna Lee. From 1994 to 1995 he played the supporting role of Detective Constable Michael Skelton in Cracker. Between roles, Johnson worked for a local undertakers, driving the hearse and acting as a pallbearer. At one funeral, a mourner recognised him from Cracker and asked for his autograph.

In 2000, he appeared in the BBC One television pilot Waking the Dead, as Detective Sergeant Spencer Jordan, a member of a specialised police unit tasked with investigating "cold cases". Waking the Dead returned for a complete series in 2001, and Johnson was a main cast member until the series ended in 2011. From 2000 to 2002, he appeared as Steve Robinson in Paul Abbott's popular drama series Clocking Off. From 2001 to 2002, he appeared as a main cast member in two series of the BBC's Babyfather.

Johnson was previously married to model and Writer Alexandra Spiegel from 2001 to 2010, with whom he shares four of his children: step-daughter Mischa, son Joachim River (JJ), and twin daughters Rain and Zillah-May.

In 2004, Johnson played the title character in the Royal Lyceum Theatre Company's Othello.

In 2010, he appeared in In a Better World (film) as 'Dr. Najeeb'.

In Nov 2011, Johnson appeared as 'Sean Dolan' a Consultant paediatrician in BBC One's Holby City.

In 2013, he also co-produced with Christian Ashaiku a film called "Disorientated Generation" (about a Nigerian man living in London). The film was partially funded by Enfield Council, with a small grant from UK Film Council. The film was originally shot in 2006.

In 2012 it was announced that Johnson would be joining Emmerdale as single father Dominic "Dom" Andrews in the later part of the year. On 23 February 2014, it was announced that he would be leaving the show later this year following the death of his character's daughter, Gemma (Tendai Rinomhota).

In 2016, Johnson was cast as the Earl of Kent in the Talawa Theatre Company and Royal Exchange Manchester co-production of King Lear. Johnson received praise for his performance, with the Guardian writing "giving depth to straight simplicity" and the Manchester Theatre Awards saying that "... wrongest servant Kent is played with passion and often with humour by Wil Johnson".

He also performed in a play, called ‘The Swallowing Dark’ at the Liverpool Playhouse and Theatre 503. In 2011, he also starred as gangster boss Big Mike in Anuvahood and in 2008 as Big Man in Adulthood