The Theotokis family's geographical origin has two unconfirmed versions, one of which places the origin in Byzantium, while the other claims Athens as a likely origin.

The most widespread version of the Byzantine origin claims that the Theotoki family abandoned Constantinople during the fall of the city in 1453. A branch of the family then settled in Athens where they remained until 1686 after which they followed Francesco Morosini to Nafplion. When Nafplion was occupied by the Ottomans, some members of the family were arrested and sent back to Constantinople while those who managed to escape settled in Corfu.

According to Eugenios Rizos Ragavis, the most distinguished members of the Theotokis family (Corfu branch) were Nikiforos Theotokis, archbishop of Kherson and Astrakhan; Count Spyridon Georgios Theotokis, president of the Senate of the Ionian islands; Baron Ioannis Antonios; Ioannis Baptist Theotokis, a prominent member of Filiki Eteria and a fighter in the Greek War of independence; and his grandson George Theotokis, Prime Minister of Greece.

Following the fall of Constantinople, another part of the family escaped to Crete; the great painter Dominikos Theotokopoulos (El Greco) came from this branch. Finally, a third branch of the Theotokis family took refuge in Chios, where there are descendants to this day.