Metrophanes II served as Bishop of Cyzicus in Asia Minor when he was called to join the delegation of bishops attending the Council of Florence. He was appointed by the Emperor John VIII in May 1440 as successor to Patriarch Joseph II of Constantinople following the death of the latter in Florence. The Emperor was eager to secure help from Pope Eugene IV to deal with Turkish aggression, so he forced the patriarch and all other bishops to submit to papal authority. Only one bishop did not submit: Markos Eugenikos, Metropolitan of Ephesus, and without his signature the document of Union between East-West fell inactive. For his submission to the Union, he was nicknamed Mitrofonos (Mother-Killer), deposed by a popular uprising and fled to the Papal court in Rome.
Metrophanes died in Constantinople on August 1, 1443.