Originally the home of Antonio Grimani (doge from 1521 to 1523), the current building is the result of architectural interventions carried out between 1532 and 1569 on commission of the heirs, Vittore, procurator of San Marco, and Giovanni, patriarch of Aquileia.
Above all, the latter intervened directly in the design, perhaps using suggestions from Sanmicheli (to whom the entire building was attributed in the past), but above all referring to the treatise of Sebastiano Serlio. The result is that of a very valuable and admirable architecture that blends elements of the Venetian tradition and the Tuscan-Roman one: among others, the evocative environment of the tribune with the pyramidal skylight is striking. The fusion of different artistic cultures is also found in the marvelous pictorial decorations of the staircase and of the rooms on the first floor, where painters such as Federico Zuccari, Francesco Salviati, Giovanni da Udine, Lambert Sustris and Camillo Mantovano worked.
The palace housed the art and archeology collections of Cardinal Domenico Grimani and Giovanni, patriarch of Aquileia, who were also donors of substantial parts of their collections to the Republic, which were at the basis of the birth of the public statuary of the Serenissima . The historical-artistic aspect of the monument reflects the taste and cultural policy of the Grimani family who played their fortune - social, economic, political - right between the two fundamental centers of Venice and Rome.
This makes Palazzo Grimani unique in the Venetian context, comparable in cultural importance, while distinguishing between private and public commissions, to the works of Jacopo Sansovino for the area of Piazza San Marco, for the realization of which, moreover, it was fundamental to contribution of this family.