Isabella was born circa 1216/1217 as the only of King Leo I of Armenia and his second wife, Sybille of Cyprus. She had an elder half-sister named Stephanie, who died in 1220 leaving behind a young son who died not much later. She was still in infancy when she was betrothed to the third son of King Andrew II of Hungary, but the marriage never took place.

Her father died 2 May 1219, and he named Isabella as his heir. He had originally named his great-nephew Raymond-Roupen as his heir, and he released the barons from their oath of allegiance to him. Raymond-Roupen was not about to let it go easy, and he contested Isabella’s claim. Nevertheless, Isabella was proclaimed Queen by the nobles under the regency of Adam of Baghras, who was murdered after just a few months. The regency was then granted to Constantine of Barbaron, a powerful Armenian noble. Raymond-Roupen managed to invade but was eventually forced to withdraw. He was captured alongside his mother after a three-month siege and died in captivity. His mother was eventually exiled.

Armenia was now badly weakened and in need of a strong ally. The Principality of Antioch was a strong ally and suggested that one of the sons of Bohemond IV of Antioch should marry Isabella. Philip of Antioch swore to uphold the rites of the Armenian Apostolic Church and Armenian customs and married Isabella, still a child, at Sis in June 1222. He was then crowned King. However, his reign was not to last long. He was unpopular, and the regent Constantine of Barbaron ended up revolting at the end of 1224. Philip and Isabella were captured en route to Antioch and promptly taken back to Sis. Philip was imprisoned, and he died of poisoning in 1225, leaving Isabella free to marry again.

However, Isabella did not want to marry again, and she fled to Silifke Castle where she sought refuge with the Hospitallers, a Catholic military order. They ended up selling Silifke Castle with her still in it to the regent. Philip’s father was enraged by his son’s death, and he sought the help of Kayqubad I, the Seljuq Sultan of Rûm, who raided part of the country in 1225. The regent had a new husband for Isabella in mind and forced her to marry his own son in June 1226. His son was subsequently crowned King Hetum I, but Isabella reportedly refused to consummate the marriage for several years – she was after all still only in her early teens.

They eventually had children together, though the order and exact amount of children are unknown. She probably shared her power with her husband and died in 1252, still in her early 30s. She was buried in the Monastery of Trazarg. She was succeeded by her son, named for her father, who became King Leo II. The area of the Kingdom of Armenia is part of present-day Turkey.