Although recognized as the first Renaissance tomb by a Lombard artist, the funerary monument of Medea Colleoni remains inadequately studied. This paper aims to reveal the tomb’s innovative character by a close analysis of its design, heraldry, epitaph, iconography, and other relevant literary and visual sources. Medea Colleoni was an illegitimate daughter of Bartolomeo Colleoni, captain general of the Venetian army from 1455 to 1475, and one of the richest men of his time. Soon after her death in 1470, the general commissioned her tomb from the Milanese artist Giovanni Antonio Amadeo. The author proposes for the first time that Amadeo was influenced by a particular type of Florentine tomb design pioneered by Bernardo and Antonio Rossellino who mitigated the sharp separation of the sacred figures from the human. Amadeo pushed beyond his Tuscan sources by bringing the Madonna and Child, Saint Catherine of Alexandria, and Saint Catherine of Siena into the center of tomb close to Medea’s effigy. By so doing, Amadeo created a unique female-centered monument that legitimates Medea’s identity as the daughter of Bartolomeo Colleoni, while also projecting an extraordinary image of her piety.