Dating back to pre-Roman times, the town of Pavia (then known as Ticinum) was a municipality and an important military site (a castrum) under the Roman Empire. It was said by Pliny the Elder to have been founded by the Laevi and Marici, two Ligurian tribes, while Ptolemy attributes it to the Insubres. The Roman city most likely began as a small military camp, built by the consul Publius Cornelius Scipio in 218 BC to guard a wooden bridge he had built over the river Ticinum, on his way to search for Hannibal, who was rumoured to have managed to lead an army over the Alps and into Italy. The forces of Rome and Carthage ran into each other soon thereafter, and the Romans suffered the first of many crushing defeats at the hands of Hannibal, with the consul himself almost losing his life. The bridge was destroyed, but the fortified camp, which at the time was the most forward Roman military outpost in the Po Valley, somehow survived the long Second Punic War, and gradually evolved into a garrison town.

Its importance grew with the extension of the Via Aemilia from Ariminum (Rimini) to the Po River (187 BC), which it crossed at Placentia (Piacenza) and there forked, one branch going to Mediolanum (Milan) and the other to Ticinum, and thence to Laumellum where it divided once more, one branch going to Vercellae - and thence to Eporedia and Augusta Praetoria - and the other to Valentia - and thence to Augusta Taurinorum (Turin) or to Pollentia.

Here, in 476, Odoacer defeated Flavius Orestes after a long siege. To punish the city for helping the rival, Odoacer destroyed it completely. However, Orestes was able to escape to Piacenza, where Odoacer followed and killed him, deposing his son Romulus Augustus. This is commonly considered the end of the Western Roman Empire.

A late name of the city in Latin was Papia (probably related to the Pope), which evolved to the Italian name Pavia. Sometimes it's been referred to as Ticinum Papia, combining both Latin names.

Under the Ostrogoths, Pavia became a fortified citadel and their last bulwark in the war against Belisarius.

After the Lombards conquest, Pavia became the capital of their kingdom (568-774). During the Rule of the Dukes, it was ruled by Zaban. It continued to function as the administrative centre of the kingdom, but by the reign of Desiderius, it had deteriorated as a first-rate defensive work and Charlemagne took it in the Siege of Pavia (June, 774) assuming the kingship of the Lombards. The Hungarians burned Pavia from sometime during 889 to 955 Ad. Pavia remained the capital of the Italian Kingdom and the centre of royal coronations until the diminution of imperial authority there in the 12th century. In 1004 Henry II, Holy Roman Emperor bloodily suppressed a revolt of the citizens of Pavia, who disputed his recent crowning as King of Italy.

In the 12th century Pavia acquired the status of a self-governing commune. In the political division between Guelphs and Ghibellines that characterizes the Italian Middle Ages, Pavia was traditionally Ghibelline, a position that was as much supported by the rivalry with Milan as it was a mark of the defiance of the Emperor that led the Lombard League against the emperor Frederick Barbarossa, who was attempting to reassert long-dormant Imperial influence over Italy.

In the following centuries Pavia was an important and active town. Under the Treaty of Pavia, Emperor Louis IV granted during his stay in Italy the Palatinate to his brother Duke Rudolph's descendants. Pavia held out against the domination of Milan, finally yielding to the Visconti family, rulers of that city in 1359; under the Visconti Pavia became an intellectual and artistic centre, being the seat from 1361 of the University of Pavia founded around the nucleus of the old school of law, which attracted students from many countries.

The Battle of Pavia (1525) marks a watershed in the city's fortunes, since by that time, the former cleavage between the supporters of the Pope and those of the Holy Roman Emperor had shifted to one between a French party (allied with the Pope) and a party supporting the Emperor and King of Spain Charles V. Thus during the Valois-Habsburg Italian Wars, Pavia was naturally on the Imperial (and Spanish) side. The defeat and capture of king Francis I of France during the battle ushered in a period of Spanish occupation which lasted until 1713 at the conclusion of the War of the Spanish Succession. Pavia was then ruled by the Austrians until 1796, when it was occupied by the French army under Napoleon. During this Austrian period the University was greatly supported by Maria Theresa of Austria and saw a great renaissance that eventually led to a second renaissance due to the presence of leading scientists and humanists like Ugo Foscolo, Alessandro Volta, Lazzaro Spallanzani, Camillo Golgi among others.

In 1815, it again passed under Austrian administration until the Second War of Italian Independence (1859) and the unification of Italy one year later.