While attending New York University's Tisch School of the Arts, she became active in experimental theater, planning to pursue it after earning a master's degree in the Interactive Media Program of the School of Cinematic Arts at the University of Southern California.

Indie Fund is a group that invests in the development of independent video games and is a TED fellow.

[4] She moved to Los Angeles in 2003 when she was 24, and studied towards a master's degree in the Interactive Media Program of the School of Cinematic Arts at the University of Southern California.

[9] Upon graduating, Santiago and Chen founded thatgamecompany in May 2006, with a contract with Sony Computer Entertainment to develop three games for the PlayStation Network.

[13][14] For the studio's third game, Journey, thatgamecompany hired Robin Hunicke as the producer, allowing Santiago to focus more on directing the company as a whole.

[16] During the development of Journey, in 2009, Santiago became a TED fellow, giving a talk at a USC conference where she discussed whether video games were art, which was responded to a year later by Roger Ebert.

[17] Santiago was one of the backers of the Indie Fund, started in March 2010, a group which invests in the development of independent video games.

[23] In October 2015, following the sale and dissolution of the company, Santiago left Ouya for Google Play Games.

Through this she hopes to change the rest of the industry to also approach making videogames as a "creative medium" rather than a product.