Probably born in Luini, by Lake Maggiore. Possibly by 1499 (when Leonardo left) he had come to Milan where he was influenced by Bramantino, Andrea Solario and, increasingly, by Leonardo whose manner he superficially adapted to a conservative taste. At least three of his compositions appear to derive from Leonardo designs (The Virgin and S. Anne in the Ambrosiana; Christ among the Doctors in the National Gallery, London; and Christ carrying the Cross in the Poldi Pezzoli Museum, Milan), and many of his works have borne attributions to Leonardo (The Virgin and Child with a Columbine).

Because of a dearth of dated works, and his stylistic consistency, there is no satisfactory chronology for his easel paintings. More is known concerning his many commissions for decorations in churches and villas in the Milanese, from the earliest in 1512 for frescoes in the abbazia at Chiaravalle, to the last of 1529-32 for frescoes in S. Maria degli Angeli, Lugano. Luini received payment in 1531 for frescoes executed at Saronno, but a payment of July 1532 for work at Lugano was made to his heirs. It is assumed he died in 1532, probably in Milan.