Vassal of the Uesugi Clan, became head of the Yamayoshi Clan in September of 1577, at the death of his brother Yamayoshi Toyomori at the age of 13 with his uncle as his guardian. According to Uesugi Clan customs, a clan's land is seized until its head reaches adulthood at the age of 15, whereupon it is returned, but taking into account the long service of the Yamayoshi Clan, only half of the Yamayoshi land was seized, and Kagenaga was transferred from Sanjou Castle to Koba Castle.

The year after he entered Koba Castle, Kenshin died and the Otate no Ran began. He held Koba Castle in Uesugi Kagekatsu's name.

He also supported Kagekatsu in the Shibata Shigeie Rebellion and thereafter fought in many of Kagekatsu's wars, including Toyotomi Hideyoshi's assault against Odawara Castle and the Imjin War.