During his reign he was in conflict with the Burids, from whom he captured Emesa in 1138. Later that year, Byzantine emperor John II Comnenus besieged Aleppo, after he had brought the Crusader Principality of Antioch under Byzantine control. This siege was unsuccessful, and Zengi turned his attention to Damascus in 1139. Damascus allied with the Crusader Kingdom of Jerusalem against him, and he was unable to take the city.
In 1144 Zengi besieged the Crusader County of Edessa. Edessa was the weakest and least Latinized Crusader state, and Zengi captured it on December 24, 1144. This event led to the Second Crusade, and later Muslim chroniclers noted it as the start of the jihad against the Crusader states.
Though he continued his attempted to take Damascus, Zengi was assassinated by a slave in 1146. In Aleppo he was succeeded by his son Nur ad-Din.