Kagekatsu was the second son of Nagao Echizen no Kami Masakage (d.1564), husband of Uesugi Kenshin's elder sister Ayahime. As a child he was known as Kiheiji. Kenshin adopted him and named him part heir alongside Uesugi Kagetora (Hôjô Ujiyasu's 7th son, adopted by Kenshin in 1569). Following Kenshin's death in 1578 Kagekatsu found a pretext to feud with Kagetora and the resulting civil war became known as the Otate no ran. By 1579 Kagekatsu had gained the upper hand and forced Kagetora to commit suicide. This bloody division allowed Oda Nobunaga's generals (headed by Shibata Katsuie) to conquer the Uesugi's lands in Kaga, Noto, and Etchû. In 1582 Kagekatsu led an army into Etchû and was defeated by Oda forces at the Battle of Tenjinyama. He hastily returned to Echigo when he learned that Oda general Mori Nagayoshi had raided Echigo in his absence. When Uzu Castle in Etchû fell to the Oda, in the course of which a number of important Uesugi retainers were killed, Kagekatsu's fortunes appeared bleak. The Uesugi were given a reprieve with the death of Nobunaga shortly afterwards. Kagekatsu made friendly overtures to Hashiba (Toyotomi) Hideyoshi, and attacked Shibata Kasuie's northern outposts during the Shizugatake Campaign (1583). He was therfore confirmed in his Echigo fief (worth 550,000 koku) and went on to support Hideyoshi during the Komaki Campaign (1584), in which he played a limited role by launching a foray into Shinano. He attacked Hôjô forts in Kôzuke during the 1590 Odawara Campaign and in 1598 was transferred to Aizu (worth almost 1,000,000 koku), an area of western Mutsu controlled by the Ashina prior to 1589. That same year he was named one of Five Regents (Go-Tairo) and following Hideyoshi's death grew hostile to Tokugawa Ieyasu. In 1600 Kagekatsu began preparations for war, and in effect opened the Sekigahara Campaign. His army, which Ishida Mitsunari had hoped would tie down Tokugawa Ieyasu himself, clashed with the forces of Date Masamune and Mogami Yoshiakira and gained little in the battles conducted in and around Aizu. After the Tokugawa victory at the Battle of Sekigahara, Ieyasu transferred the Uesugi fief to Yonezawa and reduced their income to around 300,000 koku. Kagekatsu was able to redeem himself somewhat by taking part in the Osaka Castle campaigns. At the Battle of Shigeno (1614) Kagekatsu led 5,000 men into action against the Osaka defenders and distinguished himself by refusing an offer by Ieyasu to retire for rest. Kagekatsu, who died at Yonezawa in 1623, was remembered as a dour, humorless man. Although considered a capable enough general, his record was clearly an uneven one.

Kagekatsu was succeded by his son Sadakatsu (1603-1645).