The English-born actress will provide both voice and motion-capture for the heroine's origin story.
Luddington is known for playing Kate Middleton in William & Kate, as well as roles in Californication and the next season of True Blood.
"It's an honour… People love Lara and there is such a huge fanbase that you don't want to disappoint," she said.
"You hope people can embrace the change and re-imagining of her and at the end of the day just have fun playing the game."
Crystal Dynamics studio director Darrell Gallagher added: "This has been one of the most important jobs for us to get right.
"This Tomb Raider game is very different to any other and we are demanding far more from the voice acting than ever before as we take the franchise in a new direction."
Luddington will join the development team at panels at Nerd HQ and Comic-Con in July.
The game was recently embroiled in controversy over an apparent rape attempt scene which was later clarified by the developer.
Tomb Raider will be available on Xbox 360, PS3 and PC from March 5, 2013 worldwide.
> Read our latest preview of Tomb Raider
Watch the E3 2012 trailer for Tomb Raider below: