Baptised on 5 October 1712 in Venice, one of three brothers; his father, Domenico Guardi (1678-1716), was a minor artist and his mother was Viennese. His sister married G. B. Tiepolo in 1719. His earlier work consisted of figure subjects, often produced in collaboration with his older brother Gian Antonio (1699-1760); they have yet to be satisfactorily distinguished. In 1757 he married a painter, Maria Mathea Pagani (1726-69).

He had probably turned to painting topographical views in the earlier 1750s; by 1764 he was (doubtfully) described as 'a good pupil of the famous Canaletto'. Certainly Canaletto's works, or engravings from them (Venice: a Regatta on the Grand Canal and Venice: the Giovedi Grasso Festival in the Piazzetta from the studio of Canaletto), influenced his earlier views, but by the 1770s Guardi had evolved a distinctive style in which topography seems to take second place behind the description of light effects made with a nervous brush. Perhaps his capricci best embody this poetic concern.

He died in Venice on January 1793. The dearth of securely dateable views prevents the establishment of a satisfactory chronology, and the issue is further complicated by the many repetitions he made of his compositions; unlike Canaletto, he appears not to have maintained a studio practice. His son Giacomo (1764-1835) continued less competently in his father's manner.