Born in 1525 as the second son of Takeda Nobutora, head of the Kai Takeda. His elder brother became Takeda Shingen. Their father doted on Nobushige and planned to make him heir, but in 1541 Shingen exiled their father and took the headship. Nobushige never rebelled; instead, he served loyally as Shingen's right hand and deputy commander, earning the sobriquet 'Koten-kyu' from his court title of Sama-no-suke. In 1558, he gave his eldest son Nobutoyo the '99 Articles of Takeda Nobushige,' a code of warrior conduct that was widely read in later centuries and acclaimed as a masterpiece. On September 10, 1561, at the Fourth Battle of Kawanakajima, he fought heroically to protect Shingen's headquarters from the Uesugi onslaught and was killed in action at age 37. Shingen grieved deeply, and the loss profoundly affected his subsequent campaigns.

Warm, sincere, and accomplished in both letters and arms. Though he could have claimed the headship, he deferred to his brother and remained a paragon of loyalty. Some say he was even more respected by retainers than Shingen.

His '99 Articles' were widely read throughout the Edo period as a guide to samurai self-cultivation, and Nobushige became the ideal of a 'true warrior.' Sanada Masayuki is said to have named his second son 'Nobushige' (later known as Yukimura) out of admiration for Takeda Nobushige.