When the Spanish–American War broke out he raised the 71st New York Volunteer Infantry and was commissioned as its colonel on May 2, 1898. He was quickly promoted to brigadier general of Volunteers on May 27, 1898. He commanded the second Philippine Expeditionary Force which became the 2nd Brigade, 2nd Division, VIII Corps. Greene took a prominent part in the Battle of Manila in 1898. He assisted in the surrender negotiations for Manila. In August 1898 he was promoted major general of Volunteers and resigned on February 28, 1899. During his service, he was put in charge of the finances of the preliminary Philippine administration. In September 1898, he briefed President McKinley on the Philippine situation and recommended the annexation of the entire archipelago.