Genoa started expanding during the First Crusade. At the time the city had a population of about 10,000. Twelve galleys, one ship and 1,200 soldiers from Genoa joined the crusade. The Genoese troops, led by noblemen de Insula and Avvocato, set sail in July 1097. The Genoese fleet transported and provided naval support to the crusaders, mainly during the siege of Antioch in 1098, when the Genoese fleet blockaded the city while the troops provided support during the siege. In the siege of Jerusalem in 1099 Genoese crossbowmen led by Guglielmo Embriaco acted as support units against the defenders of the city.

The Republic's role as a maritime power in the Mediterranean region secured many favorable commercial treaties for Genoese merchants. They came to control a large portion of the trade of the Byzantine Empire, Tripoli (Libya), the Principality of Antioch, Cilician Armenia, and Egypt. Although Genoa maintained free-trading rights in Egypt and Syria, it lost some of its territorial possessions after Saladin's campaigns in those areas in the late 12th century.