Rossellino was trained by Filippo Brunelleschi (Brunelleschi, Filippo) and was influenced by Luca della Robbia (Della Robbia, Luca) and Lorenzo Ghiberti (Ghiberti, Lorenzo). His style exhibited a moderate classicism, as observed in an early tabernacle (1449, Sant'Egidio, Florence). Rossellino's masterpiece, the tomb of Leonardo Bruni (Bruni, Leonardo) (1444–50) in Santa Croce, Florence, was executed for that eminent chancellor and inaugurated a new type of sepulchral monument that ranks with the greatest achievements of early Renaissance sculpture. The work, establishing a fine balance between sculpture and architecture, figure and decoration, became the prototypical wall monument of its time. Other significant works include the tomb of Orlando de' Medici (1456–57) in Santissima Annunziata, Florence, and the Tomb of the Blessed Villana delle Botte (1451–52) in Santa Maria Novella, Florence.

As an architect, Rossellino worked for Pope Nicholas V (Nicholas V), who employed him (1451–53) on the building of St. Peter's (Saint Peter's Basilica) in Rome, for which he designed the apse, and for Pope Pius II (Pius II). From his uncompleted reconstruction of Pienza, the pope's native city (renamed from Corsignano), the cathedral and the Piccolomini Palace (1460–63) are two of his most celebrated works. Although the extent of Rossellino's contribution to the project's design has not been fully determined, he was closely associated with this monument of Renaissance urban planning.