As a condottiere (mercenary leader), he was commander in the Florentine (1443–1448 and 1452) and Neapolitan (1448–1452) armies.
[1] After inheriting the seigniory of Imola after the death of his father, Guidantonio Manfredi, he struggled long with his uncle Astorre II Manfredi, who held Faenza.
In 1467, after having been besieged in Imola by Alessandro and Costanzo Sforza, he fought in the Battle of Molinella.
In 1471, his son Guidoriccio rebelled against him, and Manfredi was imprisoned under the authority of the Milanese general Roberto da Sanseverino.
The following year, he sold the city for 40,000 ducats to Cardinal Pietro Riario, who ceded it to Girolamo Riario.