Bessarion was born in Trebizond, the Black Sea port in northeastern Anatolia that was the heart of Pontic Greek culture and civilization during the Byzantine and Ottoman periods.

[8] Under Pletho, he "went through the liberal arts curriculum…, with a special emphasis on mathematics…including the study of astronomy and geography" that would have related "philosophy to physics…cosmology and astrology" and Pletho's "mathematics would include Pythagorean number-mysticism, Plato's cosmological geometry and the Neoplatonic arithmetic which connected the material world with the world of Plato's Forms.

In 1436 became abbot of a monastery in Constantinople and in 1437, he was made metropolitan of Nicaea by the Byzantine Emperor John VIII Palaeologus, whom he accompanied to Italy in order to bring about a reunion between the Eastern (Orthodox) and Western (Catholic) churches.

Bessarion participated in the Byzantine delegation to the Council of Ferrara-Florence as the most eminent representative of unionists, although he originally belonged to the party of anti-unionists.

On 6 July 1439, he read the declaration of the Greek Association of Churches in Florence cathedral, in the presence of Pope Eugene IV and the Emperor John VIII Palaeologus.

[11] However, Gill upholds Bessarion's sincerity in being convinced to the truth of the Roman position in the matters discussed at the Council quoting from Bessarion's own work Oratio Dogmatica: But if we had discerned error in the doctrine of the Latins or distortion in their faith, not even I would have counseled you to embrace union and agreement with them in that case, that for fear of bodily ills you should prefer the values of the present world to spiritual values, the freedom of the body to the betterment of the soul, but I myself would have undergone all that is worst and I would have exposed you to it before I would have urged you to union with them and have recommended such action.

He is known in history as the original patron of the Greek exiles (scholars and diplomats) including Theodore Gaza, George of Trebizond, John Argyropoulos, and Janus Lascaris.

For these efforts, his fellow humanist Aeneas Silvius Piccolomini, then Pius II, gave him the purely ceremonial title of Latin Patriarch of Constantinople in 1463.

His work, by opening up the relations of Platonism to the main questions of religion, contributed greatly to the extension of speculative thought in the department of theology.