Theodor (who had been crowned emperor under the name Peter) made him his co-ruler after Asen was murdered in 1196. A year later, Theodor-Peter was also assassinated, and Kaloyan became the sole ruler of Bulgaria.

Kaloyan's expansionist policy brought him into conflict with the Byzantine Empire, Serbia and Hungary. King Emeric of Hungary allowed the papal legate who delivered a royal crown to Kaloyan to enter Bulgaria only at the Pope's demand.

Kaloyan took advantage of the disintegration of the Byzantine Empire after the fall of Constantinople to the crusaders or "Latins" in 1204. He captured fortresses in Macedonia and Thrace and supported the local population's riots against the crusaders. He defeated Baldwin I, Latin emperor of Constantinople, in the Battle of Adrianople on 14 April 1205. Baldwin was captured; he died in Kaloyan's prison. Kaloyan launched new campaigns against the Crusaders and captured or destroyed dozens of their fortresses. He was thereafter known as Kaloyan the Roman slayer, because his troops murdered or captured thousands of Romans.