Born in Florence to a family of weavers, Penni entered Raphael's workshop very early in his life, and collaborated with him on several works, including the famous Rooms of the Vatican Palace,[5] as well as the frescoes of Villa Farnesina, both in Rome. Heinrich Wölfflin and some other writers credited him with the entire execution of the Raphael Cartoons, with Raphael only creating the initial design, though more recent writers believe Raphael did much of the work himself.
In 1526, he left Rome and joined back up with Giulio Romano, who had arrived in Mantua in 1524. According to Vasari, he was not well received in Mantua (though he did work with Romano on the frescoes at the Palazzo Te) and so soon began a long journey to Naples via Lombardy and Rome. He died in Naples in 1528. His pupils included Leonardo da Pistoia (Grazia).