Son of Mori Yoshinari, lord of Kaneyama Castle in Mino, and elder brother of Mori Ranmaru. When Nobunaga seized Karasumine Castle in 1565, Yoshinari became its lord and renamed it Kaneyama Castle; after Yoshinari was killed at the Battle of Usayama in 1570, the 13-year-old Nagayoshi inherited the headship and became lord of Kaneyama. He developed the castle town's commerce, including the Kanayama river port on the Kiso River and periodic markets, while also campaigning as a fierce general feared as the "Demon Musashi." He was killed in action at the 1584 Battle of Komaki-Nagakute.

Despite inheriting his domain at the adversity of age 13, he showed real skill in governance, while on the battlefield he was known for a ruthless decisiveness so fierce that he was feared as the "Demon Musashi."

After Nagayoshi's death, the lordship of Kaneyama Castle passed to his younger brother Mori Tadamasa, who was later transferred to Matsushiro in Shinano and then Tsuyama in Mimasaka, after which Kaneyama Castle was abandoned. The town layout Nagayoshi developed at Kanayama forms the basis of the present-day streetscape of the Kanayama district in Kani City, Gifu Prefecture.