William was the son of Geoffrey I Villehardouin. In 1236 he aided the Latin Empire against the Byzantine Empire of Nicaea, and was rewarded with the overlordship of the Venetian Duchy of the Archipelago and other Venetian territories in the Aegean Sea. In 1239 he married the daughter of Narjot de Toucy and of Narjot's first wife (who was the daughter of the dowager empress Anna). William came to power in Achaea in 1246 when his brother Geoffrey II Villehardouin died.
As prince he conquered the remaining territory of the Peloponnese (known at the time as Morea) and built the fortress of Mistra near Sparta. In 1249 he captured Monemvasia with help from his Euboean vassals, and later that year accompanied Louis IX of France on the Seventh Crusade, joining him in Cyprus with 400 knights and 28 ships. Louis also gave him a license to mint coins in the style of royal French money.
Under William's rule the Duchy of the Archipelago, the Duchy of Athens, and the Venetian lords of Euboea recognized him as their lord. In 1255 his Venetian second wife Carintana dalle Carceri died, leading to a dispute over the inheritance of a fief in Euboea, and war broke out between Venice and Achaea (the Guerre des terciers de l'Eubée, the "War of the Terciers of Euboea," terciers being the three Venetian lords of the island). William won the war and also defeated the Duke of Athens in 1258, reaffirming his influence over the duchy.
In 1259 he married Anna Komnene Doukaina, daughter of Michael II of Epirus, forming an alliance with the Byzantine Despotate of Epirus against Nicaea, an alliance which also included Manfred of Sicily. In September of that year he led the Achaean forces at the Battle of Pelagonia against the Nicaeans, but the Epirote army deserted and William was defeated. He fled the field and hid under a haystack, where he was captured and brought to Nicaea. He remained in captivity until 1262, and was forced to hand over Monemvasia and Mistra to the Byzantine Empire, which had been restored in Constantinople the previous year.
William had now lost all of his previous power, as had his former lord, Baldwin II of Constantinople, whose Latin Empire was lost with the Byzantine restoration. William and Baldwin both acknowledged Charles of Anjou as lord of Achaea under the Treaty of Viterbo in 1267; Charles had earlier defeated and killed William's old ally Manfred. As a vassal of Charles, William and 400 Achaean knights fought against Conradin at the Battle of Tagliacozzo in 1268.
William and Anna had two daughters, Isabella and Margaret; Isabella, the elder daughter, married Charles's son Philip of Sicily, who, however, predeceased his father. Charles personally succeeded William in 1278, ending the Villehardouin dynasty and setting up Angevin rule, with the principality governed essentially as a province of the Kingdom of Naples. With the decreasing power and influence of Achaea, the Duchy of Athens became the most powerful state in Greece.