Santiago made her television debut in 2000 in the syndicated action/adventure television series Queen of Swords, playing Tessa Alvarado/The Queen. She went on to appear on television shows including the first 11 episodes of the first season of the sitcom Good Morning, Miami, playing Lucia Rojas-Klein; and in episodes of Kitchen Confidential, Curb Your Enthusiasm, and One on One. In 2001, Santiago landed a co-starring role with Annabeth Gish and Kamar de los Reyes in the VH1 TV-movie The Way She Moves, playing Christina Juarez, a Latina Dancer with the dream of winning a dance exhibition. Santiago then played Sarah Marshall in the independent film The Way Back Home. In 2009, she starred in the movie The Cell 2, a direct-to-video spin-off of the 2000 film The Cell, playing psychic investigator Maya Casteneda. She was a cast regular on the 2010 TV series Twentysixmiles, playing Jennifer Calderon. She also had a role in the 2010 film Angel Camouflaged playing Desdemona. She guest starred in an episode of the TV series Royal Pains in 2010, reuniting with her former Good Morning, Miami co-star, Mark Feuerstein. She appeared in 3 episodes of the TV series The Secret Life of the American Teenager in 2012.