Shigenaga fought at the Battle of Kawanakajima as rearleft wing commander, acting as Uesugi Kenshin's retainer. However, in 1568-1569 after the Kawanakajima campaign he briefly rebelled against Kenshin and allied himself to Takeda Shingen, Kenshin's nemesis, because Shigenaga felt dissatisfied by his small reward compared with his achievement. He first murdered Nagao Fujikage, Uesugi's vassal, and captured his castle. This betrayal forced Kenshin to lay siege to Murakami castle held by Shigenaga Honjo. The conflict proved costly for Kenshin as Irobe Katsunaga, one of his generals, was slain in the battle and could not take the castle easily. In spite of his rebellion against Kenshin, which lasted for one year, Takeda Shingen did not help him and Shigenaga was forced to surrender to Kenshin under the coordination of the Ashina clan. After the siege he was pardoned by Kenshin and later fought at Battle of Tedorigawa againts Oda Nobunaga Forces. After the death of Kenshin in 1578 Shigenaga supported Uesugi Kagekatsu as successor during the Siege of Otate. In 1588, Shigenaga once again entered conflict against the Mogami clan and Date clan wherein he defeated a Mogami army at the battle of Jugorihara. When Mogami Yoshiaki expanding his territory into the Shōnai region in Dewa province and threatened Yoshiuji Daihoji, who sought aid from Shigenaga. Together they successfully recovered the Shōnai region as a territory of the Uesugi clan. In 1598, Uusegi Kagekatsu was transferred to Aizu Wakamatsu castle by the Toyotomi government, and Shigenaga was transferred to the Aizu region. Later on, during the conflict between the Toyotomi loyalists and Tokugawa Ieyasu, Shigenaga fought in a series of battles once again against Date Masamune and Mogami Yoshiaki at the Siege of Hasedō and Battle of Matsukawa. Date's forces attacked several times including a defense against a rear attack, despite Date's attempt to attack from Mount Shinobu. In October 6, Shigenaga resisted an attack from Date Masamune's warriors, such as Katakura Kagetsuna, Oniniwa Tsunamoto and Yashiro Kageyori. His forces successfully killed several of Kagetsuna's famous soldiers, forcing Date Masamune to stop attacking and return whilst Shigenaga was successful in defending Fukushima Castle from the invading Eastern coalition.
Honjō Shigenaga was particularly known as the wielder of the famous blade Honjo Masamune, a katana representing the Shogunate during most of the Tokugawa Era. Shigenaga was attacked by Umanosuke who already possessed a number of trophy heads. Shigenaga was attacked with the Honjo Masamune which split his helmet, but he survived and took the sword as a prize. The blade was kept by Shigenaga until he was sent to Fushimi Castle, during the Bunroku era, or around 1592 to 1595. Shigenaga ran out of funds and was forced to sell the sword to Toyotomi Hidetsugu, Toyotomi Hideyoshi's nephew and retainer. It was bought for 13 Mai, 13 O-Ban, which was 13 large gold coins.
