[4] He began his career as an architect in Bologna, supporting himself by painting and making perspective templates for inlay craftsmen.

He made his first trip to Rome in 1536 to make measured drawings of Roman temples, with a thought to publish an illustrated Vitruvius.

In 1558, he was in Piacenza to revise the designs of Palazzo Farnese, commissioned by Margaret of Austria, wife of the Duke Ottavio Farnese and daughter of Emperor Charles V. From 1564 Vignola carried on Michelangelo's work at St Peter's Basilica,[4] and constructed the two subordinate domes according to Michelangelo's plans.

Designs by Vignola, in company with Baldassare Peruzzi, Giulio Romano, Andrea Palladio and others furnished material for an exhibition in 2001[6] His two published books helped formulate the canon of classical architectural style.

The earliest, Regola delli cinque ordini d'architettura ["Canon of the five orders of architecture"] (first published in 1562, probably in Rome), presented Vignola's practical system for constructing columns in the five classical orders (Tuscan, Doric, Ionic, Corinthian and Composite) utilising proportions which Vignola derived from his own measurements of classical Roman monuments.