The city of Mantua was founded, probably around 2000 BC, on the banks of the Mincio, on a sort of island which provided natural protection. In the 6th century BC it was an Etruscan village which, in Etruscan tradition, was re-founded by Ocno.

The name derives from the Etruscan god Mantus, of Hades. After being conquered by the Cenomani, a Gallic tribe, the city was conquered by the Romans between the first and second Punic wars, confusing its name with Manto, a daughter of Tyresia (Tiresias). The new territory was populated by veteran soldiers of Augustus. Mantua's most famous ancient citizen is the poet Publius Vergilius Maro, Virgil (Mantua me genuit), who was born near the city in 70 BC.

After the fall of the Roman Empire, Mantua was invaded in turn by Byzantines, Longobards and Franks. In the 11th century it became a possession of Boniface of Canossa, marquis of Toscana. The last ruler of the family was the countess Matilda of Canossa (d. 1115), who, according to legend, ordered the construction of the precious Rotonda di San Lorenzo (1082). After the death of Matilde of Canossa, Mantua became a free commune, and strenuously defended itself from the Holy Roman Empire in the 12th and 13th centuries. In 1198 Alberto Pitentino optimised the course of the Mincio, creating what Mantuans call "the four lakes" to reinforce the city's natural protection. Between 1215 and 1216 the city was under the podesteria of the Guelph Rambertino Buvalelli.

During the struggle between the Guelphs and the Ghibellines, Pinamonte Bonacolsi took advantage of the chaotic situation to seize power in 1273. His family ruled Mantua for the next century, making it more prosperous and artistically beautiful. On August 16, 1328, the last Bonacolsi, Rinaldo, was overthrown in a revolt backed by the House of Gonzaga, a family of officials. Luigi Gonzaga, who had been podestà of the city in 1318, was elected "People's Captain". The Gonzaga built new walls with five gates and renovated the architecture of the city in the 14th century, but the political situation in the city did not settle until the third Gonzaga, Ludovico I Gonzaga, eliminated his relatives, seizing power for himself.

Through a payment of 120,000 golden florins in 1433, Gianfrancesco I was appointed marquis of Mantua by Emperor Sigismund, whose daughter Barbara of Brandenburg he married. In 1459 Pope Pius II held a diet in Mantua to proclaim a crusade against the Turks. Under Francesco II the famous Renaissance painter Andrea Mantegna worked in Mantua as court painter, producing some of his most outstanding works. The first duke of Mantova was Federico II Gonzaga, who acquired the title from Emperor Charles V in 1530. Federico commissioned Giulio Romano to build the famous Palazzo Te, on the periphery of the city, and profoundly improved the urbanistic asset of the city.
About Mantua, the poet Torquato Tasso in 1586 wrote: "This is a very beautiful city and one worth travelling a thousand miles to see". In 1624 Francesco IV moved the ducal seat to a new residence, the Villa della Favorita, designed by the architect Nicolò Sebregondi.

In 1627, the direct line of the Gonzaga family came to an end with the vicious and weak Vincenzo II, and the town slowly declined under the new rulers, the Gonzaga-Nevers, a cadet French branch of the family. The War of the Mantuan Succession broke out, and in 1630 an Imperial army of 36,000 Landsknecht mercenaries besieged Mantua, bringing the plague with them. Mantua never recovered from this disaster. Ferdinand Carlo IV, an inept ruler whose only aim was to hold parties and theatrical representations, allied with France in the Spanish Succession War. After the latter's defeat, he took refuge in Venice, carrying with him a thousand pictures. At his death, in 1708, he was declared deposed and his family lost Mantua forever in favour of the Habsburgs of Austria. Under Austrian rule, Mantua enjoyed a revival, and during this period the Royal Academy of Sciences, Letters and Arts, the Scientific Theatre, and numerous Palaces were built.

On June 4, 1796, during the Napoleonic Wars, Mantua was besieged by Napoleon as a move against Austria, who joined the First Coalition. Austrian and Russian attempts to break the siege failed, but spread the French thin enough to abandon the siege on 31 July to fight other battles. The siege resumed on August 24. In early February the city surrendered and the region came under French administration. Two years later, in 1799, the city was retaken by the Austrians. Later, the city was again passed to Napoleon's control. In the year 1810 by Porta Giulia, a gate of the town at Borgo di Porto (Cittadella), Andreas Hofer was shot; he had led the insurrection of the Tyrol against Napoleon.

After the brief French rule, Mantua returned to Austria in 1814, becoming one of the Quadrilatero fortress cities in northern Italy. Agitation against Austria culminated in a revolt which lasted from 1851 to 1855, and was finally suppressed by the Austrian army. One of the most famous episodes of Italian Risorgimento took place in the small valley of Belfiore, when a group of rebels was hanged by the Austrians. In 1866, Mantua was incorporated in united Italy by the king of Sardinia.