In 1554, he married the daughter of Hōjō Ujiyasu (Lady Hayakawa) as part of the Kai-Sagami-Suruga Alliance.

Ujizane inherited family headship in 1558, when his father retired in order to focus his attention on the Imagawa advance into Tōtōmi and Mikawa Provinces.

In 1560, Yoshimoto was killed in the Battle of Okehazama, the province of Totomi and Mikawa went into chaos.

This had little effect because Uesugi Kenshin took the opportunity to sell salt to the Takeda and only resulted in the downfall of the Imagawa clan.

After his defeat in the 1569 Siege of Kakegawa, Imagawa Ujizane allied himself with Ieyasu in return for help in recovering his territory in Suruga Province.