DeFrancesco was born on January 18, 1965, and grew up outside of Philadelphia, Pennsylvania, United States. By the time he was 14, he was already performing in local Philadelphia jazz clubs with his father. At the age of 18, he had achieved recognition on the Philadelphia scene for his blues vocals and guitar playing.
In 1997, DeFrancesco joined the faculty of Berklee College of Music in Boston, Massachusetts, where he taught a number of notable guitarists, including John Mayer. He currently resides in Philadelphia and performs with his group the Johnny DeFrancesco Power Trio.