Born in 1551 as the eldest son of Kaneko Motonari in Niihama District, Iyo Province (today Niihama City, Ehime), Motoie belonged to the Kaneko clan — provincial lords descended from the Musashi Seven Bands' Murayama line who had held sway there for some 300 years. At 19 he married a daughter of Ishikawa Michikiyo, and the couple had four sons and a daughter. When Toyotomi Hideyoshi launched his conquest of Shikoku in 1585, castle after castle around him surrendered to the Mori-Kobayakawa forces, but Motoie refused to bow, unwilling to switch allegiance twice in as many days. Facing Kobayakawa Takakage's army of some 30,000 with barely 600 men of his own, he made his stand at Takatoge Castle near Himi. As the situation grew hopeless, on May 16, 1585, he set fire to the castle himself and led about 100 men in a final charge onto the plain of Nonoichigahara, fighting to the death at age 35. His fierce final stand reportedly moved even his enemy commander Takakage, who is said to have honored him with a proper burial.

A man of unbending principle who refused opportunistic surrender even against overwhelming odds. His choice to burn his own castle and charge to his death rather than yield came to embody the pride of Iyo's local warrior clans, and is still remembered in the region today.

The ruins of Kaneko Castle are preserved as a Niihama City historic site, with a memorial marking Motoie's dramatic last stand. He remains a symbol of the fierce local resistance to Hideyoshi's conquest of Shikoku.