Tessie Santiago is a first generation American. Her parents and grandparents fled from Cuba after Fidel Castro took power of the country in the early 1960s. Her grandfather was a Sculptor. Santiago's father, Joe Santiago, was a musician and her mother's mother was described as a Painter. (Santiago's mother, Tess Stebbins, went on to earn a college degree from Barry University as a working adult in Florida and is Executive Director of Medical Education at the University of Miami Miller School of Medicine.) Santiago learned to play the piano at age seven.

Santiago has two younger siblings, a brother and a half-sister. She attended Miami Coral Park High School graduating class of 1993.

A May 1999 graduate from the University of Miami, she earned a double major in film and theater arts and was able to study Shakespeare in London, England and Film Production with the Faculty of Film and Television of Academy of Performing Arts (FAMU) in Prague, Czech Republic. She has always immersed herself in creative endeavors. At university, she starred in the independent film Echo and became the resident “It Girl,” acting in many student films.

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.

She was ranked #50 on the Maxim Hot 100 Women of 2001 list.

Santiago wed actor Carlos Bernard in December 2013.