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 which throws a deep shadow on the top of the facade. Michelangelo revised the central window in 1541, adding an architrave to give a central focus to the facade, above which is the largest papal stemma, or coat-of-arms with papal tiara, Rome had ever seen. When Paul appeared on the balcony, the entire facade became a setting for his person. The courtyard, initially open arcades, is ringed by an academic exercise in ascending orders (Doric, Ionic and Corinthian). The piano nobile entablature was given a frieze with garlands, added by Michelangelo.

On the garden side of the palace, which faced the River Tiber, Michelangelo proposed the innovatory design of a bridge which, if completed, would have linked the palace with the gardens of the Vigna Farnese, Alessandro's holding on the opposite bank, that later became incorporated into the adjacent villa belonging to the Chigi family, which the Farnese purchased in 1584 and renamed the Villa Farnesina.[6] While the practicalities of achieving this bridge remain dubious, the idea was a bold and expansive one.

During the 16th century, two large granite basins from the Baths of Caracalla were adapted as fountains in the Piazza Farnese, the "urban" face of the palace. The palazzo was further modified for the papal nephew Ranuccio Farnese by Jacopo Barozzi da Vignola. It was completed for the second Cardinal Alessandro Farnese by Giacomo della Porta's porticoed facade towards the Tiber which was finished in 1589. Following the death of Cardinal Odoardo Farnese in 1626, the palazzo stood virtually uninhabited for twenty years. At the conclusion of the War of Castro with the papacy, Duke Odoardo was able to regain his family properties, which had been sequestered. The resulting inventory is the oldest surviving complete inventory of Palazzo Farnese.

After Odoardo's death, Pope Alexander VII allowed Queen Christina of Sweden to lodge in the palace for several months, but she "proved a tenant from hell". After her departure for Paris, the papal authorities discovered that her unruly servants not only had stolen the silver, tapestries, and paintings, but also had "smashed up doors for firewood" and removed sections of copper roofing. Several main rooms were frescoed with elaborate allegorical programs including the Hercules cycle in the Sala d'Ercole or the Hercules Room, the "Sala del Mappamondo" or The Room of Maps, and the well known The Loves of the Gods (1597–1608) in the Farnese Gallery, both by the Bolognese painter Annibale Carracci. Other rooms have frescoes by Daniele da Volterra and by other artists.

For generations, the room with Herculean frescoes accommodated the famous Greco-Roman antique sculpture known as the Farnese Hercules. Other works from the family collection of classical sculpture were also housed in the palace. One of the vault and ceiling fresco by Annibale Carracci is Galleria Farnese, an art gallery. According to Ann Sutherland Harris, "The Galleria frescoes make even more extensive use of ancient sculptural and architectural sources, and in addition take their basic structure from two ceilings by the most prestigious artists of the High Renaissance in Rome, the Loggia of Psyche by Raphael and Michelangelo's Sistine Chapel ceiling". Carracci adopted the quadri riportati, which the ceiling is divided into units and turned it into a collection of framed paintings, along with the cast masks among the garlands, and carved putti, and sculptures supporting the central scene. This large central scene depicts the triumphal progress of Bacchus and Ariadne. Two smaller paintings are attached to the top and bottom of the central picture, and two vertical pictures on either side, filled with sphinxes, Pan, and two satyrs.