The film was originally set up at Metro-Goldwyn-Mayer under the title Breaking Vegas, with Brett Ratner attached to direct; the original book title 'Bringing Down the House' couldn't be used because of a 2003 comedy film with the same name.

Other titles considered for the project included Beat the House, The System, and Beginner's Luck before Sony Pictures acquired it and renamed it 21; Shawn Levy was also offered the chance to direct before Robert Luketic took over.

Filming of 21 began in March 2007, with Las Vegas scenes shot at the Planet Hollywood Resort & Casino, the Red Rock Casino, and the Hard Rock Casino.

Since MIT did not allow filming on its campus, all MIT school and dorm interiors, the gymnasium, and the alumni reception scenes were actually shot at Boston University.

The film sparked a race-based controversy because most characters were portrayed as White Americans despite the real MIT Blackjack Team, as depicted in the source book, being mainly Asian American; producer Dana Brunetti stated they lacked access to bankable Asian-American actors for the leads.

Jeff Ma, the real-life inspiration for lead character Ben Campbell and a consultant on the film, was criticized online as a 'race traitor' for not insisting his character be Asian-American, though he said he had no control over casting decisions.

Lead actor Jim Sturgess, who is from London, required a dialect coach to master an American accent for the role.

The closing scene's track, 'Rito a Los Angeles' by Giuseppe De Luca, features part of the main riff of 'In-A-Gadda-Da-Vida' and was also used in the Ocean's Eleven sequel Ocean's Twelve, another Las Vegas casino heist film.

Despite fears that Las Vegas casinos would resist a film explaining card-counting techniques, casino operators including MGM Resorts saw the film as a promotional draw that would encourage more visitors to try their luck in Vegas.