Architectural features of the main facade include the alternating triangular and segmental pediments that cap the windows of the piano nobile, the central rusticated portal and Michelangelo's projecting cornice.

The cornice is by Michelangelo, other parts completed by Giacomo della Porta (Italian, 1537-1602) and Giacomo Barozzi da Vignola (Italian, 1507-1573). Michelangelo took over from Antonio da Sangallo (ii) as architect to Paul III at the Palazzo Farnese, despite the bitter opposition of Sangallo's relatives and supporters. At the Palazzo Farnese, Michelangelo gave the decisive final direction to the exterior cornice and to the upper levels of the courtyard. The design for the cornice was tested in March 1547 in the form of a full-scale wooden model of one corner hoisted into position. Annibale Carracci painted the ceiling of the Palazzo Farnese's gallery (1597-1601). The Galleria Farnese is a long and relatively narrow room (20.14 x 6.59 m) covered by a barrel vault.