When the original leader of the Fourth Crusade, Count Thibaud of Champagne, died in 1201, Boniface was chosen as its new leader. Boniface's family was well established in the east; his oldest brother William was the father of King Baldwin V of Jerusalem, and his brother Conrad was active in the Third Crusade.
Boniface was a cousin of Philip of Swabia, who was married to Irene, a sister of the deposed Byzantine emperor Isaac II Angelus. After the Crusade was diverted to Zara, Boniface travelled to Swabia to meet with Philip, and while there also met with Alexius Angelus, Isaac II's son, who had escaped from the custody of his uncle Alexius III Angelus. It was here that the idea of diverting the Crusade further to restore Alexius as Alexius IV was likely first discussed. Both Boniface and Alexius travelled separately to Rome to ask for Pope Innocent III's blessing for the endeavour; however, Boniface was specifically told by Innocent not to attack any Christians, including the Byzantines.
After the conquest of Constantinople in 1204, Boniface was assumed to be the new emperor, both by the western knights and the conquered Byzantine citizens. However, the Venetians vetoed him, believing that he already had too many connections in the Empire (and, likely, felt that they would not have as much influence in the new Empire if Boniface was in control). Instead, they chose Baldwin of Flanders. Boniface founded the Kingdom of Thessalonica and also held territory in Crete, though he later sold Crete to the Venetians. He was killed in an ambush by the Bulgarians on September 4, 1207, and his head was sent to Bulgarian Tsar Kaloyan.