Upon his father's death in 1541, a number of the Hōjō's enemies sought to take advantage of the opportunity to seize major Hōjō strongholds. Ōgigayatsu Tomosada tried unsuccessfully to take Edo Castle (江戸城), and a few years later, in 1545, an army led by Ashikaga Haruuji (足利 晴氏) and Uesugi Norimasa (上杉 憲政) besieged Kawagoe Castle (see Siege of Kawagoe (1545)). Hōjō Tsunashige (北条 綱成), the stepson of Ujiyasu's brother Tamemasa (北条 為昌) and son-in-law of Ujitsuna, was outnumbered 3,000 to allegedly 80,000, and Ujiyasu led a relief force of 8,000 soldiers. Ujiyasu slipped a samurai past the enemy lines to inform Tsunashige of the enemy's approach, and made use of ninja to learn of the enemy's strategy and attitude. Using this intelligence, he led a night attack against the Ashikaga/Uesugi force. Despite being vastly outnumbered, the Hōjō army defeated the besiegers because, under Ujiyasu's orders, they were not bulked down by heavy armor, and were not slowed down by seeking to take heads. This battle proved the end of the Ōgigayatsu Uesugi (扇谷上杉家) line and destroyed the prestige of Norimasa of the Yamanouchi Uesugi clan (山内上杉家) as the Governor-General of Kantō region (Kantō kanrei (関東管領?)), until Uesugi Kenshin (上杉 謙信), who had subsequently been adopted by Norimasa, assumed the post in 1561.
Hōjō Ujiyasu expanded the Hōjō territory, which now covered five provinces, and managed and maintained what his father and grandfather had held. He took Kōnodai in Shimōsa Province in 1564 following a battle against Satomi Yoshihiro (里見 義弘). Towards the end of his life he saw the first major conflicts between his own clan and Takeda Shingen (武田 信玄), who would become one of the greatest warlords of the period. As a response to Hōjō's intervention in his invasion of Suruga Province, Shingen came into Musashi Province from his home province of Kai, attacking Hachigata and Takiyama Castles, where Ujiyasu's sons repulsed them. However, despite the intact castles behind him, Shingen pressed on to the Hōjō central home castle of Odawara (小田原城), burning the castle town and withdrawing after three days. Two of Ujiyasu's seven sons fought Takeda at the battle of Mimasetoge in 1569, ending the first of the Takeda campaigns against the Hōjō.
Subsequently, Ujiyasu managed to make peace with Uesugi Kenshin and Takeda Shingen, the most powerful adversaries of Hōjō, letting his seventh son be adopted by childless Kenshin and accepting the fait accompli of Shingen's reign over Suruga. To cement the ties of Takeda-Imagawa-Hojo, Ujiyasu also gave his two daughters to those two clans; Lady Hayakawa was made as Imagawa Ujizane's wife while Lady Hojo (Hojo Fujin) was made as Takeda Katsuyori's second wife. Ujiyasu died in 1571, passing on the Hōjō domains to his eldest son Ujimasa (北条 氏政) in a relatively favourable situation.
- Turnbull, Stephen (2002). War in Japan: 1467-1615, Oxford: Osprey Publishing.