Having joined the Fourth Crusade about 1201, he distinguished himself at the sieges of Constantinople and elsewhere. During the July 1203 siege, Henry was one of eight division generals, the others including Boniface of Montferrat (the crusade leader), Doge Enrico Dandolo (leader of the Venetians), Louis of Blois (one of the first nobles to take the cross), and Henry's own brother, Baldwin of Flanders, who controlled the largest division. During the 1204 siege, Henry led a chevauchée expedition to gain supplies and raided a castle in Philia, near the Black Sea with, according to Robert de Clari, about 30 knights and an unspecified number of mounted sergeants. An ambush was laid for him by Emperor Alexius V "Murzuphlus" Ducas, but Henry and his force routed the Greeks soundly, captured a revered icon supposedly containing relics of Christ, and returned to the crusader camp. He soon became prominent among the princes of the new Latin Empire.
When his elder brother, the emperor Baldwin I, was captured at the Battle of Adrianople in April 1205 by the Bulgarians, Henry was chosen regent of the empire, succeeding to the throne when the news of Baldwin’s death arrived. He was crowned August 20, 1205.
Henry was a wise ruler, whose reign was largely passed in successful struggles with Kaloyan, Tsar of Bulgaria, and with his rival, Theodore I Lascaris, emperor of Nicaea. He later fought against Boril of Bulgaria (1207-1218) and managed to defeat him the Battle of Plovdiv (1208). Henry appears to have been brave but not cruel, and tolerant but not weak, possessing "the superior courage to oppose, in a superstitious age, the pride and avarice of the clergy." The emperor died, poisoned, it is said, by his Bulgarian wife Maria of Bulgaria, on June 11, 1216. He had previously been married (in 1204) to Agnes of Montferrat, daughter of Boniface of Montferrat, the Crusade leader, but she had died (probably in childbirth) before her father's death in 1207.
Some contemporary historians say that Henry made a peace with Bulgarians after the death of Tsar Kaloyan. Years later Pope Innocent III ordered that he should contract a marriage with Kaloyan's only child, his daughter Maria. Henry's only child by his first wife Agnes apparently died in childbirth with his mother, and this second marriage also left no heirs.