Jorge was born Guillermo Santana on 13 June 1951 in Autlán, in Jalisco, Mexico. His parents were Josefina and Jose Santana. Jose was a musician. Jorge started playing guitar in San Francisco when he was a teen.

He was a member of the San Francisco-based, Latin-rock band Malo, who had a top twenty hit in the U.S. Billboard Hot 100 with “Suavecito” in 1972. He released two solo albums on Tomato Records, Jorge Santana and It’s All About Love, featuring former Malo members. In the mid-1970s he played with the Fania All-Stars. The band, Malo, which means “bad” in Spanish, played a combination of laid-back fusion of jazz, rock and a variety of forms of Latin music, similar to the sound of Carlos Santana, his brother. The band’s debut album, called “Malo” was released in 1972 and included the song “Suavecito”. The song, which had a smooth, melodic sound, made it to No.18 on the Billboard singles chart, and became a popular song for fans of Latin rock. Malo played together for four years and produced four albums until they broke up and Santana embarked on a solo career and played with the New York-based band the Fania All-Stars.

In 1994 he recorded an album with his brother and Carlos Santana’s nephew, Carlos Hernandez, called Santana Brothers.

He died in San Rafael, California of natural causes on 14 May 2020, aged 68. He was survived by his brother Carlos and another brother, Antonio. He also had four sisters: Lety Santana, Laura Porras, Irma Santana, and Maria Vrionis. He was married to Donna with whom he had a son, Anthony and a daughter, Michelle. He also had one grandson.