When his elder brother, Emperor Baldwin, 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 20 August 1206.

Upon Henry's ascension as Latin emperor, the Lombard nobles of the Kingdom of Thessalonica refused to give him allegiance. A two-year war ensued and after defeating the Templar-supported Lombards, Henry confiscated the Templar castles of Ravennika and Zetouni (Lamia).

Henry was a wise ruler, whose reign was largely passed in successful struggles with Tsar Kaloyan of Bulgaria and with his rival Emperor Theodore I Lascaris of Nicaea. He later fought against Boril of Bulgaria (1207–1218) and managed to defeat him in the Battle of Philippopolis. Henry campaigned against the Nicean Empire, expanding a small holding in Asia Minor (at Pegai) with campaigns in 1207 (at Nicomedia) and in 1211–1212 (with the Battle of the Rhyndacus), where he captured important Nicean possessions at Nymphaion. Though Theodore I Laskaris could not oppose this later campaign, it appears that Henry decided it best to focus on his European problems, for he sought a truce with Theodore I in 1214, and amicably divided Latin from Nicean possessions to the favour of Nicea.