Born in Upper Manhattan, New York to Dominican parents, Santana's career in show business began with a push from his parents who wanted to keep him off the tough streets of New York. He began his career at the age of three as an advertising model for a fast food chain. His first screen appearance was as an extra in the Woody Allen film, The Purple Rose of Cairo.

In 1991, Santana landed a recurring role on The Cosby Show as Stanley, the faithful admirer of the young Rudy Huxtable and the romantic rival of Rudy's friend Kenny (Deon Richmond). He was then cast as Marcus Dixon in the short lived sitcom, Getting By, starring Cindy Williams and Telma Hopkins. Deon Richmond was cast as his brother Darren, due to their interaction on The Cosby Show.

In 1995, Santana was cast as Marcus Henry in the short-lived CBS family drama Under One Roof, co-starring with James Earl Jones, Joe Morton and Vanessa Bell Calloway. From 1996 and 1999, he played the role of Ohagi on Moesha.

In 1996, he landed the role of Romeo Santana on The Steve Harvey Show. In 2001, he played the role of Jermaine in the movie Flossin . In 2002, he appeared in the VH1 TV movie, Play'd: A Hip Hop Story with Toni Braxton. That same year, Santana landed a role in the Eddie Murphy's comedy, Showtime. His last television acting role was on the UPN series, Half & Half, His last film role was a 2003 comedy, The Blues with fellow Cosby Show alum Deon Richmond.

On November 9, 2002, Santana was shot and killed while sitting in a parked car in South Los Angeles. He was 26 years old. Santana was buried on November 18, 2002 at Saint Raymond's Cemetery in The Bronx, New York.

Damien Andre Gates was later convicted of the first-degree murder of Santana and the attempted murder of another man in the car, and was sentenced to three consecutive life sentences plus 70 years in prison. Brandon Douglas Bynes received a 23-year sentence after pleading guilty to voluntary manslaughter and assault with a deadly weapon. An officer involved in the case testified that Monique King, reportedly Gates' girlfriend and aged 15 at the time of Santana's death, falsely claimed that Santana had tried to rape her, which prompted Gates and Bynes to attack the car. Other reports say that King played a part in the shooting because Santana was having an affair (or cheating) on her with another party. King received eight years in juvenile custody.