Born in 1538 as the second son of Hojo Ujiyasu, the 3rd head of the Go-Hojo clan. He became heir after his elder brother's early death and succeeded as the 4th head in 1559 upon his father's retirement. He married Obaiin, daughter of Takeda Shingen, upholding the tripartite Takeda-Imagawa-Hojo alliance. Building on his father's domain, he expanded into northern Kanto to create the Go-Hojo's largest territory. In 1590, however, Toyotomi Hideyoshi's Odawara Campaign brought roughly 220,000 troops against Odawara Castle. After a three-month siege, Ujimasa surrendered and was ordered to commit seppuku by Hideyoshi, ending roughly 100 years of Go-Hojo rule over the Kanto. He was 53.

A steady lord who inherited his father Ujiyasu's prudent approach. At times overly cautious in diplomacy, he excelled in domain administration and devoted himself to the welfare of his people.

He built the Go-Hojo's largest domain but misjudged his response to Hideyoshi, leading to the clan's destruction. The Odawara Campaign symbolizes the end of the Sengoku era, and 'Odawara hyojo' became a byword for indecisive deliberation.