In 1991, Santana landed a recurring role on The Cosby Show as Stanley, the boyfriend of Rudy Huxtable and the 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 November 1994, Santana appeared on Sister, Sister as Joey, in which he falls in love with Tia and Tamera (Tia and Tamera Mowry) at Rocket Burger.
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. Between 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 had a role in the Eddie Murphy comedy Showtime. His last television acting role was on the UPN series, Half & Half; his last film role was a 2003 comedy film, The Blues with Deon Richmond.
On November 9, 2002, Santana was shot in the head and killed as he and his best friend, former child actor Brandon Quintin Adams were in a car leaving another man's home in the Crenshaw District of Los Angeles. Damien Andre Gates fired the shot that entered through the trunk of the vehicle in which Santana was a Passenger. The bullet penetrated the right-front Passenger headrest and entered Santana's head, killing him instantly. Damien was convicted of the first-degree murder of Santana and the attempted murder of Adams 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, even though none of the shots fired from his revolver entered the vehicle. An officer involved in the case testified that Monique King, reportedly Gates's girlfriend and aged 15 at the time of Santana's death, falsely claimed that Santana made sexual advances towards her, which prompted Gates' and Bynes' attack. King was found guilty of second-degree murder and attempted murder but acquitted on two murder charges, receiving ten years in Juvenile custody. Santana was 26 years old at the time of his death. He was buried on November 18, 2002, at Saint Raymond's Cemetery in The Bronx, New York.