The actress will play a 60-year-old with early-onset Alzheimer's disease, according to Entertainment Weekly.
The character will reportedly be keeping a dark secret from Cal Lightman (Tim Roth) and his team.
O'Toole is known for her role as Martha Kent on Smallville and for playing love interest Lana Lang in Superman III. She has also featured in episodes of Law & Order and Nash Bridges.
The second season of Lie To Me concludes on September 13. The crime drama will return to Fox on November 10.