Born Yoroku in 1559 at Sakado Castle, Echigo Province, Naoe Kanetsugu was the son of Higuchi Kanetoyo, a senior Nagao Masakage retainer. Upon reaching adulthood, he married his cousin Osen, widow of Uesugi retainer Naoe Nobutsuna, and assumed leadership of the Naoe family. He entered service as a koshō (page) to Uesugi Kenshin, distinguishing himself through intellect and loyalty. Following Kenshin's death, Kanetsugu served as karō (senior retainer) to Kenshin's adopted son Kagekatsu Uesugi, becoming a key clan strategist.

Kanetsugu fought in significant battles early in his career, including the 1577 Battle of Tedorigawa and the 1590 Odawara Campaign. His tactical skill emerged during conflicts along the Sea of Japan coast against Sassa Narimasa and Maeda Toshiie. After Toyotomi Hideyoshi's 1598 death, Tokugawa Ieyasu accused Kagekatsu of rebellion over castle construction. Kanetsugu responded by authoring the infamous "Naoe-jo," a scathing letter criticizing Ieyasu's motives and integrity. This act provoked Ieyasu's Aizu Campaign and escalated tensions toward the Battle of Sekigahara.

During the Sekigahara campaign, Kanetsugu advocated pursuing Tokugawa forces directly, but Kagekatsu prioritized suppressing Date Masamune and Mogami Yoshiaki in the north. Kanetsugu commanded Uesugi forces at the Siege of Hasedō Castle against Date troops, achieving tactical success before withdrawing upon learning of the Western Army's Sekigahara defeat. After the Uesugi clan's surrender, their domain shrank from 1.2 million koku in Aizu to 300,000 koku in Yonezawa. Kanetsugu implemented economic reforms: expanding rice production through land development and flood control, increasing yields to 510,000 koku; promoting local specialties like safflower and wax; inviting mining engineers; and allowing lower-ranking samurai to farm part-time.

Diplomatically, Kanetsugu secured clan survival by forging ties with Tokugawa insiders, notably arranging his daughter's marriage to Honda Masanobu's son Masashige. This earned the Uesugi exemption from obligatory Tokugawa military service. Kanetsugu was characterized by unwavering justice and strategic foresight. When Hideyoshi visited Uesugi territories with minimal guards, Kanetsugu rejected councilors' assassination suggestions, arguing exploiting Hideyoshi's trust would bring eternal shame. He believed conflicts should first be resolved honorably through negotiation. His nickname "Warrior of Love" stemmed from the prominent 愛 (ai, "love") kanji on his helmet, symbolizing compassion toward enemies and civilians, and devotion to his wife Osen (later Teishin-ni). The emblem reminded troops to maintain ethical conduct.

Kanetsugu revered Kenshin as his foundational mentor and served Kagekatsu with unshakeable loyalty, prioritizing clan preservation post-Sekigahara. His deep friendship with Sanada Yukimura and Ishida Mitsunari, cemented during the Odawara Campaign, formed an oath-bound brotherhood. He mourned Mitsunari intensely after Sekigahara, requiring Kagekatsu's intervention to refocus on protecting the Uesugi lineage. Facing the painful Tokugawa transition, Kanetsugu reluctantly campaigned against former allies like Yukimura at Osaka Castle. Kagekatsu comforted him, urging him to honor Yukimura's resolve through continued service. Kanetsugu died on January 23, 1620, survived by his wife, who helped raise Uesugi Sadakatsu before her death in 1637.