Craig appeared in his first screen role in 1992, playing an Afrikaner in The Power of One. Having played minor roles in the miniseries Anglo-Saxon Attitudes and the shows Covington Cross and Boon, he appeared in November 1993 as Joe in the Royal National Theatre's production of Tony Kushner's Angels in America. Also in 1993, Craig was featured in two episodes of the American television shows Zorro and The Young Indiana Jones Chronicles, and British shows Heartbeat, in which he played Peter Begg; Between the Lines; Drop the Dead Donkey and Sharpe's Eagle. In 1994, Craig appeared in The Rover, a filmed stage production and Les Grandes Horizontales, a stage production at the National Theatre Studio, where he first met Rachel Weisz, who would become his second wife Craig was featured in the poorly received Disney film A Kid in King Arthur's Court (1995).In 1996, Craig starred in the BBC drama serial Our Friends in the North as the troubled George 'Geordie' Peacock. Appearing alongside Christopher Eccleston, Gina McKee and Mark Strong, Craig's part in the series is considered his breakthrough role.

In 2005, Craig was contacted by Eon Productions to portray James Bond. Initially, he was unsure about the role and was resistant to the producers' overtures. "There was a period of trying to woo him" longtime Bond co-producer Barbara Broccoli later commented in 2012. During this period, he sought advice from colleagues and friends, of whom "most of us said to him...'there is life after Bond'." He stated he "was aware of the challenges" of the Bond franchise, which he considered "a big machine that makes a lot of money". He aimed at bringing more "emotional depth" to the character. Born in 1968, Craig is the first actor to portray James Bond to have been born after the Bond series started and after the death of Ian Fleming, the novels' writer.

In 2022, Craig starred in a contemporary revival of Macbeth opposite Ruth Negga on Broadway. Variety described his performance writing "Craig has some strong moments but does not capture the transformation of Macbeth into a power-hungry tyrant." The Guardian's Alexis Soloski rated the production 3/5, stating, "...Craig's burly Macbeth, clad handsomely in Suttirat Larlab's modern dress costumes, is every inch a man of action and a soldier, even in a silky bathrobe, entirely convincing in motion, less persuasive when zipping through Macbeth's equivocations." Craig also starred in Glass Onion, a sequel to Knives Out. He has reportedly signed on for a third film, with Rian Johnson to direct again.

In 2007, Craig and British Prime Minister Tony Blair took part in the United Kingdom's Comic Relief charity fundraiser, ultimately raising more than USD $90 million. Craig made a cameo appearance as himself in a sketch with Catherine Tate who appeared in the guise of her character Elaine Figgis from The Catherine Tate Show, for the BBC Red Nose Day 2007 fundraising programme. Craig participated in the Broadway Cares/Equity Fights AIDS fundraising 8 December 2009, raising $1,549,953 in the 21st annual Gypsy of the Year competition, from six weeks of curtain appeals at their hit Broadway drama, A Steady Rain. Craig starred in 2011 in a short film narrated by Judi Dench, which was produced for International Woman's Day. The next year, Craig worked with Orbis International in Mongolia to raise support and awareness of the Orbis medical team and their Flying Eye Hospital.

In 2012, Craig expressed a dislike and distrust for politics and politicians in general, being quoted as saying "Politicians are shitheads. That's how they become politicians, even the good ones. We're actors, we're artists, we're very nice to each other. They'll turn around and stab you in the fucking back". He has been particularly scathing about Tony Blair, going as far as comparing Blair's penchant for befriending celebrities to the book Mephisto. He also expressed a reluctance to involve himself with politicians, arguing that by doing so "you immediately are aligning yourself with a political party."

Craig supported Barack Obama in the 2008 and 2012 US presidential elections. He was outspoken about his opposition to Brexit before the 2016 EU membership referendum. In 2016, he was pictured wearing a "Vote Remain" t-shirt which was adorned with the words, "No man is an island. No country by itself."