The earliest dated work of the Sienese painter is a Madonna and Child (1319). His presence was documented in Florentine up until 1321. He would return there after spending a number of years in Siena.
The frescoes on the walls of the "Hall of the Nine" (Sala dei Nove) or "Hall of the Peace" (Sala della Pace) in the Palazzo Pubblico of Siena are one of the masterworks of early Renaissance secular painting. The "nine" was the oligarchic assembly of guild and monetary interests that governed the republic. Three walls are painted with frescoes consisting of a large assembly of allegorical figures of virtues in the "Allegory of Good Government". In the other two facing panels, Ambrogio weaves panoramic visions of "Effects of Good Government on Town and Country", and "Allegory of Bad Government and its Effects on Town and Country". The better preserved "Well-governed town and country" is an unrivaled pictorial encyclopedia of incidents in a peaceful medieval "borgo" and countryside.
Like his brother, he is believed to have died of bubonic plague 1348. Giorgio Vasari includes a biography of Lorenzetti in his Lives.