He was the eldest son of Francesco II of Lesbos, whom he succeeded as lord of the island on 26 October 1404.
William Miller summarized Jacopo's motivation as a semi-autonomous ruler was to favor Genoese interests when they conflicted with Venetian ones, but to cooperate with both when they showed signs of uniting against his neighbors, the Ottomans.
For example, he aided Centurione II Zaccaria, Prince of Achaea against the Tocchi of Cephalonia and Zante.
[1] He had no sons, so on his death he was succeeded by his younger brother Dorino I Gattilusio.
An account by Caterino Zeno dated to 1474 names Niccolò as married to an otherwise unknown Eudoksia Valenza, sister of Theodora Megale Komnene, daughter of John IV of Trebizond, but this is debunked, as John had an only daughter.