He was consecrated only two days after the death of his predecessor, Boniface V. The vacancy was short probably because of the presence in Rome of Isaac the Armenian, who was empowered to confirm the election as the imperial exarch in Italy.

He initially supported Adaloald, the deposed Catholic king of the Lombards, but established cordial relations with Adoald's Arian rival Arioald.

Honorius actively supported the difficult Christianisation of Anglo-Saxon England and sent Birinus to convert the West Saxons, but less successful in convincing the Celts to abandon their system of computing the date of Easter.

At the Sixth Council of Toledo, Honorius urged the Visigothic bishops to continue baptizing Jews, a policy instituted by Gregory I.

",[10][11] and concluding with the decree of the XVII session that Honorius had not stopped provoking scandal and error in the Body of the Church; for he had "with unheard of expressions disseminated amidst the faithful people the heresy of the one will", doing so "in agreement with the insane false doctrine of the impious Apollinaire, Severus and Themistius".

[1] Pope Leo II's letter of confirmation of the Council commended it for it had "perfectly preached the definition of the true faith"[13] and made reference to the condemnation of his predecessor:[14] We anathematize the inventors of the new error, that is, Theodore, Bishop of Pharan, Sergius, Pyrrhus, Paul, and Peter, betrayers rather than leaders of the Church of Constantinople, and also Honorius, who did not attempt to sanctify this Apostolic Church with the teaching of apostolic tradition, but by profane treachery permitted its purity to be polluted.

As a result, Honorius would later be the subject of vigorous attacks by opponents of papal infallibility in the discussions surrounding the First Vatican Council of 1870.