Born in 1540 as the son of Honjo Fusanaga, a local lord of Honjo in Echigo's Iwafune district (present-day Murakami City, Niigata), Shigenaga made Honjo Castle (later Murakami Castle) his stronghold and served Uesugi Kenshin. In 1568, dissatisfied at receiving no reward for assassinating the Nagao brothers on Kenshin's orders, he allied with Takeda Shingen and Dewa's Daibōji Yoshimasu and rose in revolt (the Honjo Shigenaga Rebellion). Kenshin first marched into Shonai to force Yoshimasu's surrender, then besieged the isolated Shigenaga at Honjo Castle for roughly a year. Shigenaga resisted skillfully, inflicting heavy losses on the Uesugi side including the death of Irobe Katsunaga, but in 1569 surrendered through the mediation of Ashina Moriuji, handing over his heir Akinaga as a hostage and ceding part of his domain to return to Kenshin's service. He went on to serve as a senior Uesugi retainer, and at the 1600 Battle of Hasedo during the Sekigahara campaign fought fiercely against the combined Mogami-Date forces. He died in 1614 at age 75.

A fierce warrior of great martial skill who would not back down even from his own lord. His command of the year-long siege against Kenshin's much larger army won admiration from allies and enemies alike.

Honjo Castle, the stage of the Honjo Shigenaga Rebellion, was later developed as the seat of the Naito and Sakakibara clans and today survives as the Murakami Castle Ruins, a National Historic Site. Shigenaga himself remained a loyal Uesugi retainer after the rebellion, and his valiant stand at the Battle of Hasedo is still remembered today.