Early in Yoshinobu's lifetime, the Satake family was threatened from the north by Date Masamune and from the south by Hojo Ujinao; however, because he quickly pledged allegiance to Toyotomi Hideyoshi during the Siege of Odawara, he was able to retain his landholdings. Under Hideyoshi's banner, he was counted as being among the six greatest generals of the Toyotomi clan, together with Tokugawa Ieyasu, Maeda Toshiie, Shimazu Yoshihiro, Mōri Terumoto, and Uesugi Kagekatsu. After the siege of Odawara was concluded, Yoshinobu was able to extend control over the whole of Hitachi Province, and soon held over 540,000 koku of land as his private fief.
Yoshinobu enjoyed good relations with Ishida Mitsunari, and joined the western army during the Battle of Sekigahara; for this he was punished by Ieyasu, who reduced his landholdings to 180,000 koku and had him transferred to the Kubota Domain, in Dewa Province. Yoshinobu took part in the Siege of Osaka, fighting Toyotomi commanders such as Kimura Shigenari and Gotō Matabei.