Ottaviano was born in Genoa, but, like his brother, the future cardinal, Federigo, spent much of his youth at the court of Urbino, presided over by their uncle, Guidobaldo da Montefeltro.

Beginning in 1497, Ottaviano participated in an alliance with King Charles VII of France, in order to expel the Sforza family from Genoa.

When Spanish troops under Emperor Charles V sacked and occupied Genoa in 1522, Ottaviano was captured and imprisoned, first at Naples, then at Aversa, and then in the fortress of Ischia, where he died in 1524, according to some authors, by poisoning.

Contemporary historians and intellectuals remembered Ottaviano as a liberal and magnanimous prince, holding him up as a quintessential Renaissance gentleman and a pattern for rulers, as did Baldassare Castiglione who made him one of the interlocutors in The Book of the Courtier (1528).

Francesco Guicciardini, in his History of Italy (1561) records him as "certainly a prince of most excellent virtue, notable for his justice and other noble qualities, and as beloved in Genoa as any ruler could be in that city of factions, where the memory of their ancient liberties was not entirely extinguished in the minds of the citizenry.