She was known as the greatest beauty of her age in Italy, and was allegedly the model for many paintings by Sandro Botticelli, Piero di Cosimo, and other Florentine painters.

[4] The Florentine poet Politian wrote that her home was "in that stern Ligurian district up above the seacoast, where angry Neptune beats against the rocks ...

They met in April 1469, when she was with her parents at the church of San Torpete in Genoa; the doge Piero il Fregoso and much of the Genoese nobility were present.

According to legend, Simonetta quickly became popular at the Florentine court, and attracted the interest of the Medici brothers, Lorenzo and Giuliano.

At La Giostra (a jousting tournament) in 1475, held at the Piazza Santa Croce, Giuliano entered the lists bearing a banner upon which was a picture of Simonetta as a helmeted Pallas Athene, painted by Botticelli, beneath which was the French inscription La Sans Pareille, meaning "The Unparalleled One".

It is clear that Simonetta had a reputation as an exceptional beauty in Florence,[11] but Giuliano's display should be considered within the conventions of courtly love.

Giuliano de Medici was assassinated in the Pazzi conspiracy on 26 April 1478, two years to the day after Simonetta's death.

[14] This claim, however, is dismissed as a "romantic myth" by Ernst Gombrich,[11] and "romantic nonsense" by historian Felipe Fernández-Armesto: The vulgar assumption, for instance, that she was Botticelli's model for all his famous beauties seems to be based on no better grounds than the feeling that the most beautiful woman of the day ought to have modelled for the most sensitive painter.