After his breakthrough role as Dr. Chris Ramsey on the ABC soap opera Port Charles in 1997, North moved into voice acting when the show ended in 2003 and has since become best known for his video game roles as Nathan Drake in the Uncharted series, Desmond Miles in the Assassin's Creed series, Merasmus in Team Fortress 2, the Prince in Prince of Persia, Dr. Edward Richtofen in the Call of Duty franchise, Deadpool in various Marvel Comics media, the Penguin in the Batman: Arkham franchise, Captain Martin Walker in Spec Ops: The Line, David in The Last of Us, himself as one of the voices for the player character in Saints Row IV, Tony Stark in Marvel's Avengers, and Ghost in the Destiny video game series.

In animation, North voices Smokescreen on Transformers: Prime, Superboy on Young Justice, and the titular character in Blaze and the Monster Machines.

[3] He majored in journalism with a baseball scholarship at the University of North Carolina at Chapel Hill,[4][5] and spent the next year working as a reporter in New Jersey before moving to New York City to pursue a career in stand-up comedy and acting.

[4] North eventually relocated to Los Angeles, where he was cast as Dr. Chris Ramsey in the General Hospital spin-off series Port Charles in 1997.

In an interview with The Guardian, he said his time as Drake requires "a lot of imagination" because "motion capture is basically theatre in spandex; there's minimal props, and you need a willingness to make an ass of yourself".

Director J. J. Abrams had cited North's performance as Drake in the decision to cast him as a starship helmsman, as he and his son are fans of the Uncharted series.

[4][17] Nolan North has received multiple awards and nominations for his work in the Uncharted series (2007–2016), as well as other video games including Deadpool (2013), The Last of Us (2013), Assassin's Creed II (2009) and the television shows Young Justice (2010–present) and Transformers: Prime (2010–2013).