Born in what is now Minami-ku, Nagoya (situated in contemporary Aichi District, Owari Province) and serving under Oda Nobuhide, Sakuma was entrusted with the care of the young Oda Nobunaga. Unlike other retainers whose support wavered between Nobunaga and Oda Nobuyuki as clan leader, Sakuma remained steadfastly loyal to Nobunaga, and fought for him consistently.
Sakuma was called Noki Sakuma (退き佐久間), which literally means "retreating Sakuma," because of his cautious tactics. He was successful in the campaign against the Rokkaku clan and helped to suppress rebellions caused by Buddhist sects in Echizen Province and at Nagashima in Osaka.
In 1572, his 3,000-man unit formed part of the reinforcements dispatched by Nobunaga to aid Tokugawa Ieyasu's approximately 8,000 soldiers against the 30,000 led by Takeda Shingen. In the Battle of Mikatagahara Sakuma retreated after a preliminary engagement. His fellow commander Hirate Hirohide, however, who fought alongside the Tokugawa troops, lost his life, and the conflict ended with a crushing defeat of the Tokugawa-Oda alliance.:222
In 1576, after Harada Naomasa's death during the campaign against the heavily fortified and well-supplied Honganji temple in Osaka, Sakuma was chosen as Harada's replacement as commander and given troops from seven provinces placing him in command of the largest Oda-clan army among the Oda retainers. However, unlike his colleagues Akechi Mitsuhide, Shibata Katsuie or Hashiba Hideyoshi who all won battles on the fronts to which they were assigned, Nobumori made no progress against the fearless Buddhist zealots. After ten years of warring, Nobunaga had the emperor mediate a truce to end the war in 1580.
That same year, Nobunaga drafted a document containing a fifteen-point accusation against Sakuma's, including past failures with those against the Honganji. Nobunaga banished Sakuma and his son Sakuma Nobuhide to the temple on Mount Koyasan, where they were forced to spend their days in the monk lifestyle. Sakuma died in 1581 at Totsugawa in Yamato Province. He was posthumously named Doumu Keigan (洞無桂巌) and Souyu (宗佑).
Nobumori's banishment has widely been regarded as representative of Nobunaga's cold-blooded treatment against even his longest-serving retainers underscoring the clan leader's shortcomings as a military commander. Nobumori, however, had reportedly held frequent tea parties and seemed more interested in these rather than focusing on military affairs. He never devised, after all, any overarching military measures against the Honganji, even though their war had remained in a stalemate. It has also been recorded that since childhood, Nobumori had been openly critical of Nobunaga.