Born in 1556 at Sakato Castle in Ueda, Echigo Province, as the second son of Nagao Masakage, head of the Ueda Nagao clan. His mother was Sendoin, Uesugi Kenshin's half-sister. When his father drowned in 1564, he was adopted by his uncle Kenshin. Upon Kenshin's sudden death in 1578, a fierce succession war — the Otate no Ran — erupted between Kagekatsu and fellow adoptee Uesugi Kagetora (seventh son of Hojo Ujiyasu). With mediation from Takeda Katsuyori, Kagekatsu destroyed Kagetora and inherited the Uesugi headship. After submitting to Toyotomi Hideyoshi, he was appointed one of the Five Great Elders and transferred to Aizu with 1,200,000 koku in 1598. At Sekigahara in 1600 he joined the Western Army and launched an offensive against the Mogami under Naoe Kanetsugu, but withdrew upon learning of the Western Army's defeat. Tokugawa Ieyasu punished him with a massive reduction from Aizu's 1,200,000 koku to Yonezawa's 300,000 koku. He refused to dismiss a single retainer, instead embracing frugality to sustain the Uesugi clan at Yonezawa. He died there in 1623 at the age of 69. Known throughout his life for his stoic silence — rarely smiling — he is remembered as a lord of unwavering integrity.

Stoic to an extreme — tradition holds he laughed only once in his entire life. Behind his silence lay deep loyalty and indomitable will. After his domain was reduced, he refused to dismiss a single retainer. His adherence to honor, inherited from Kenshin, earned him his vassals' unwavering trust.

He inherited Kenshin's spirit of righteousness and preserved the Uesugi clan through the adversity after Sekigahara. His refusal to dismiss retainers shaped the culture of the later Yonezawa domain and laid groundwork for the reforms of Uesugi Yozan.