Antonio was presumably trained by Bernardo, whom he assisted on numerous commissions; the tomb of Neri Capponi (after 1457) is an important work by the brothers. Antonio was a master of portraiture, as is shown by the busts of Giovanni Chellini (1456) and Matteo Palmieri (1468). Probably working from life masks, he carved detailed surfaces and achieved extremely realistic likenesses.

Antonio Rossellino's greatest work is the Chapel of the Cardinal of Portugal in San Miniato al Monte, outside Florence, which is an elaborate and decorative combination of architecture and figurative sculpture. He worked in the traditions established by his brother and Desiderio da Settignano, and as his style evolved, Rossellino's figures developed strong form and intense characterization. His subtle carvings and reliefs generated a calm, gentle sentiment, and he is known for many works of the Madonna, a recurrent Renaissance theme (e.g., Madonna and Child, 1478). Other works include the Shrine of the Blessed Marcolino da Forlì (1458) and the monument of Filippo Lazzari (1464).