[1] Mitsushige was the third son of Niwa Nagashige, daimyō of Shirakawa Domain.

In 1634, he was received in formal audience by Shōgun Tokugawa Iemitsu, and received a kanji from Iemitsu's name, becoming Niwa Mitsushige, along with the courtesy title of Saikyō-no-suke and Junior Fifth Rank, Lower Grade.

Upon entering Nihonmatsu Castle in 1644, Mitsushige immediately embarked on a program to improve upon the roads and to rebuild the surrounding jōkamachi.

He also invited noted priests from Mount Kōya and Manpuku-ji to his domains to establish Buddhist temples.

He retired from public life in 1679, turning the domain over to his eldest son Niwa Nagatsugu.