Santana currently endorses PRS Guitars, and is in fact one of Paul Reed Smith's first customers. He uses a Santana II model guitar using PRS Santana III pickups with nickel covers and a tremolo, with .009-.042 gauge D'Addario strings. His Signature Series models vary greatly from this in some cases, such as the Santana SE and Santana III guitars (which have ceased production). The Santana III has covered pickups instead, and no abalone stringers between the pickups (a feature unique to his official guitar). The Santana SE guitar has 22 frets, tremolo, a basic sunburst top, and a pickguard.

Santana's guitar necks and fretboards are constructed out of a single solid piece of Brazilian Rosewood, instead of the more traditional mahogany neck/Indian rosewood fretboard combination found in stock Santana models and other PRS guitars. The Brazilian Rosewood helps create the smooth, singing, glass-like tone that he is famous for.