During the Japanese-sponsored Second Philippine Republic from 1943 to 1945, he was also Minister for Health, Labor and Public Education in the government of President Jose P. Laurel.

In 1922, Tirona was elected for the Partido Nacionalista Consolidato for the first time as a member of the Senate from the 4th District, which comprised Manila, Bataan, Laguna and Rizal.

During this time, he joined the OsRox Mission[2] that led negotiations for the independence of the Philippines with the US government, resulting in the Hare–Hawes–Cutting Act.

In the first presidential election for the Commonwealth of the Philippines on September 16, 1935, he supported the candidacy of Emilio Aguinaldo, who lost to Manuel Quezon.

During Liberation in 1945, Tirona fled with the Japanese to northern Luzon, but was subsequently arrested by the Counter Intelligence Corps due to collaborating with Japan during the occupation.