Born in 1560 in Uonuma District, Echigo Province (present-day Niigata Prefecture), as the eldest son of Higuchi Kanetoyo, a local warrior in service to the Uesugi clan. His childhood name was Yoroku. From an early age he served Uesugi Kagekatsu, the adopted heir of the great warlord Uesugi Kenshin, and proved his worth during the Otate no Ran (1578-79), a succession war within the Uesugi clan, by securing Kagekatsu's victory. In 1581 he married the widow of the late senior retainer Naoe Nobutsuna and took the Naoe family name, becoming lord of Yoita Castle and the chief administrator (karo, senior councilor) of the Uesugi domain. Under the Toyotomi regime he managed the relocation of Kagekatsu to the Aizu domain (1.2 million koku), and served in logistics during the Korean Campaigns (Bunroku-Keicho no Eki, 1592-98). In 1600 he sent a scathing written rebuke known as the Naoe Letter (Naoe-jo) in response to Tokugawa Ieyasu's demand that Kagekatsu submit to him in Kyoto, triggering Ieyasu's punitive expedition against Aizu and, indirectly, the Battle of Sekigahara. After the Uesugi were reduced from 1.2 million koku in Aizu to 300,000 koku in Yonezawa, Kanetsugu refused to dismiss a single retainer, relocating the entire retainer corps to Yonezawa. He then oversaw flood-control works along the Mogami River (the Naoe Stone Embankment), promoted industries such as ramie cloth (aoso), and laid the foundation of Yonezawa domain governance. A man of letters, he assembled the Zenrin Bunko library and promoted learning in Yonezawa. He died in Edo on the 19th day of the 12th month of Genna 5 (January 1620), at the age of 60.