The palace was built after 1516 by Alfonsina Orsini, wife of Piero dei Medici, who already owned a nearby palace, later called Palazzo Madama. The initial design was probably by Giuliano da Sangallo, although the Florentine architect Nanni di Baccio Bigio was called to Rome for the construction. When Alfonsina Orsini died, the building, already begun, was left to her brother-in-law Giovanni dei Medici, who became Pope Leo X (1513-1521). Caterina dei Medici also lived there for a certain period.
When she became Queen of France in 1533, she gave up all her properties in Italy, and the palace passed to the Medici of Florence, who sold it in 1538 to Marcantonio Palosio. In 1558 it was sold to Ludovico Lante, who continued the work by joining the building to other nearby houses he owned. Following the marriage between Marcantonio Lante and Lucrezia della Rovere, the palace was enlarged to form a single complex with the adjacent Della Rovere palace. Around the middle of the eighteenth century, the architect Carlo Murena (1713-1764), commissioned by Cardinal Federico Marcello Lante, restored the entire building.

The part that originally belonged to the Lante family has an architraved portal with corbels, on which is inscribed "Ludovicus Lantes"; on the sides are windows with grilles and a sill supported by corbels, two of which have been transformed into doors. On the first floor there are seven architraved windows on brackets, surmounted by square windows; on the second floor there are seven architraved windows, and on the third floor there are simple framed windows. The façade also has string-course cornices, while a vertical ashlar band delimits the Lante and Della Rovere parts. The inner courtyard, considered one of the most beautiful of the Renaissance, is decorated with the heraldic coats of arms of the various families that owned the palace.

The original Della Rovere part is characterised by an ashlar doorway and two windows on each side, one of which has been transformed into a door. On the first floor there are five architraved windows, while those on the other floors have simple frames; those on the fourth floor are surmounted by small windows. The palace is now owned by the Aldobrandini family.