Francesco and his brother Nicolò (1715–86) were trained under their elder brother, Giovanni Antonio Guardi (Guardi, Gianantonio). Their sister Cecilia married Giovanni Battista Tiepolo (Tiepolo, Giovanni Battista). By 1731 the brothers are recorded as collaborating in a bottega, half-studio and half-shop. Francesco does not appear to have adopted the practice of veduta view painting, on which his fame rests, before the mid-1750s or later. Perhaps he was impelled by the approaching death of his brother Giovanni and the absence of competition in this profitable field except from the aging and then unproductive Canaletto. His earliest views are almost always signed or initialed, as though to draw attention to his new artistic aims, and they seem inspired by Canaletto's own works of 30 years before.

In 1782 he depicted the official celebrations in honour of the grand duke Paul's visit to Venice, basing at least one of the compositions on contemporary engravings. Later in the year he was commissioned by the republic to make similar records of Pius VI's visit, the contract specifically forbidding such copying. He enjoyed considerable favour with the English and other foreigners and was elected to the Venetian Academy in 1784. He was an exceedingly prolific artist whose scintillating and romantic impressions of the declining city are in marked contrast to Canaletto's limpid photographic records of its architecture.