Saint Eugene I's reign was marked by his unexpected election while Pope Martin I was still in exile, leading to a complex yet significant chapter in Church history. His leadership navigated theological tensions and imperial threats, shaping the Church’s stand against Monothelitism.

The reign of Saint Eugene I, the seventy-fifth Pontiff of the Church, was notable for the events surrounding his election. He was elected head of the Church while his predecessor, Pope Martin I, was still in exile, as a prisoner of Emperor Constans II. After being elected Bishop of Rome, Pope Eugene was consecrated on 10 August AD654. However, Pope Martin died on 16 September of the following year.

The fact that Pope Martin wrote a letter to his friend in Constantinople, in which he expressed his prayers for the person who would lead the Church in Rome in his place, suggests that Pope Martin approved of Eugene as his successor. According to official Vatican records, the reign of Pope Martin I ended on 16 September AD655, and that of Pope Eugene I began on 10 August AD654.

Realizing that the exiled Pope Martin I was unlikely to return and fearing that waiting too long for him would result in the emperor appointing a Monothelite as head of the Church and pope, the Roman clergy and Church leadership had no choice but to elect a new pope to lead the Church. As a result, a quiet and elderly priest was chosen as the new head of the Church.

Immediately after his election as pope, Pope Eugene I sent envoys to Constantinople with the goal of warming relations between Rome and the emperor. However, in response to the pope's attempts to reconcile, Emperor Constans II put forward the principle that Christ had only one will even though he had two natures (human and divine). The Emperor further sent his envoys to deliver to the pope a document declaring his faith.

When the Creed was read in the Basilica of Saint Mary Major in Rome, the Roman clergy and faithful were outraged. Despite threats to exile him like Martin and to roast him alive along with his Roman supporters, Pope Martin I stood firm against the demands and refused. Relations between Rome and Constantinople deteriorated further.

Emperor Constans II did not get the chance to make good on his threats against Pope Eugene I. The capture of the city of Rhodes in 654 and Constans’ defeat at the naval battle of Phoenix in 655 stopped his aggression.

Pope Eugene I passed away on 2 June 657 AD. His mortal remains were placed to rest in St. Peter's Basilica.