Patillo's first musical endeavor was with the group Creation, later called Leon's Creation. Formed in the late 1960s, Creation was a funk group similar in style and composition to Sly & the Family Stone; they were signed to Atlantic Records. Aside from Creation, Patillo worked at times with Funkadelic and Martha & the Vandellas. In 1973, Patillo joined Santana, appearing on the albums Borboletta and Festival. He remained with Santana until 1979, launching a solo career on Word Records. He released a string of successful albums on the CCM market in the 1980s, and had his own television show on TBN called Leon and Friends.
For years, Patillo pastored the Rock House Church on the historic Queen Mary in Long Beach, California but since retired the ministry in late 2009 in favor for traveling and leading seminars across the country.