I went to English boarding schools and grew up around people very much like Soames and in a milieu very much like the Forsytes's

Lewis was born in St. John's Wood, Westminster, the son of Charlotte Mary (née Bowater) and J. Watcyn Lewis, a City broker. His paternal grandparents were Welsh. His maternal grandfather was Lord Mayor of London Ian Frank Bowater and his maternal grandmother's ancestors include Bertrand Dawson, 1st Viscount Dawson of Penn (a doctor to the royal family) and philanthropist Alfred Yarrow. Lewis was brought up an Anglican.

Lewis made several visits to the United States to visit relatives during his summers as a child. He first decided to become an actor at age 16. He was educated at the independent Ashdown House School in the village of Forest Row in East Sussex and at Eton College and graduated from the Guildhall School of Music and Drama in 1993, after which he served as a stage actor for the Royal Shakespeare Company. During his time with the RSC, he played Borgheim in Adrian Noble's production of Ibsen's Little Eyolf, as well as Posthumus in Shakespeare's Cymbeline. He has also starred in another of Ibsen's plays, Pillars of the Community.

He once worked as a telemarketer selling car alarms, a job he detested.

Lewis appeared in Robinson Crusoe 1997, He played Patrick Conner. Lewis also appeared in Jonathan Kent's production of Hamlet, playing Laertes opposite Ralph Fiennes' Hamlet. This production was seen by Steven Spielberg, who subsequently cast Lewis as Richard Winters in the HBO/BBC World War II miniseries Band of Brothers, his first role of several that required a credible American accent.

Subsequently, Lewis has played Soames Forsyte in the ITV series The Forsyte Saga (later shown as a Masterpiece Theatre miniseries) — which earned him rave reviews and further exposed him to a US audience. He returned to the US to star in Dreamcatcher, a Stephen King film about a man who becomes possessed by an evil alien. The character is American but when possessed he takes on a British accent, thus requiring Lewis to toggle between the two. On the heels of this role, he starred in Keane as a Manhattanite with a fragile mental state who is searching for his missing daughter. Despite the film's poor box-office performance, the role won Lewis rave reviews.

He played Jeffrey Archer in the satirical TV special Jeffrey Archer: The Truth. Since 2004, he has appeared in a number of films, as well as the 2005 BBC TV adaptation of Shakespeare's comedy Much Ado About Nothing, as part of the ShakespeaRe-Told season. Lewis played the role of Yassen Gregorovich in the film Stormbreaker.

In February 2006, he became a trade justice ambassador for Christian Aid, a UK charity. Later that year, he also appeared in Stephen Poliakoff's BBC drama Friends and Crocodiles. Also in 2006, he was a player for England in Soccer Aid in late May, and golfed for Europe in the All*Star Cup, in late August, both shown on ITV. On 10 November 2006 and 1 May 2009, he was guest host on BBC's Have I Got News For You.

In 2008, Lewis starred as the main character Charlie Crews in the U.S. television series Life on NBC. He starred as a police officer who had been framed for murder and held in prison for 12 years from 1995 to 2007. The series began with his exoneration and a trial reinstatement in his former position as a detective in the LA Police force after winning a 50 million dollar law suit over his wrongful internment. Detective Crews, who had studied Zen during his years in prison, closed his cases in a unique manner, as he secretly continued to track down the people who had set him up.

The show, which premiered in the United States on 26 September 2007, became a victim of the 2007–2008 Writers Guild of America strike. Only half of the first season's shows were produced. When the critically acclaimed show returned, it was shuffled from night to night. (The show won a 2008 AFI Award for best television series. Life, with its high production costs, was, perhaps, an early victim of NBC's decision to clear the way for the Jay Leno Prime Time experiment. With its loyal fans waiting for the third season to start, fans were livid when the show was cancelled with little mention, leaving story lines unfinished.