Said to be from Bitchu Province (present-day Okayama Prefecture), his given name was Ise Moritoki (Ise Shinkuro). After working as a liaison officer for the shogunate, he entered the service of the Imagawa clan through the connection of his sister, who was the wife of Imagawa Yoshitada. He mediated the succession dispute that arose after Yoshitada's death and established an independent position based at Kokuji Castle (present-day Numazu, Shizuoka) around 1476. In 1491 he defeated Ashikaga Chachimaru, the Horikoshi Kubo of Izu Province, seized control of Izu, and in 1495 (or 1493 by one account) destroyed the Omori clan and captured Odawara Castle. He then embarked on governing Sagami Province, building a firm base of power in the Kanto region as the archetypal upstart daimyo of the gekokujo (low surpassing high) era. He is also known for policies such as the 40–60 (lord–peasant) land tax ratio that treated farmers favorably, stabilizing his rule through the support of the common people. The surname Hojo was adopted in his grandson's generation, so during his lifetime he was known as "Ise Sōzui" or "Ise Shinkuro." He died in 1519 at age 88 (or 87 by some accounts).

A strategist combining sharp insight in reading situations with the decisiveness to act boldly when the moment came. Even while embodying gekokujo he applied compassionate policies toward the people he governed. He remained energetically active into old age, making full use of his long life of 88 years on both battlefield and in administration. In tradition he is imagined as a black-robed schemer, but in reality he was a pragmatist equally skilled in civil governance.

He laid the foundation for roughly 100 years of Later Hojo dominance over the Kanto region across five generations, and is the emblematic figure of gekokujo in the warring states period. His distinctive domain governance structure and peasant-oriented policies led to the Later Hojo's stable rule. Odawara Castle developed as the headquarters of the Later Hojo and continues today to draw many visitors as a tourist destination.