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Before he started in government service he was a practicing lawyer and was a professor of law at the Philippine Law School and National University.
In 1913, upon learning Manuel's excellent records, former Chief Justice Cayetano L. Arellano offered him to be his secretary of the Supreme Court.

As a politician

1917 : appointed as municipal councilor of Capiz
1919 - 1921 : elected and served as Governor of the province
1922-1934 : After his term as governor he was elected to represent their province to the 7th, 8th, and 9th Philippine Legislature where he was the Speaker of the House of Representatives.
1933: He went with Sergio Osmeña to the US in  to secure passage of the Hare-Hawes-Cutting Law. He was one of the delegates in the drafting of the 1935 Constitution.
1935 to 1938 : He also served as a member of the national Assembly
26 November 1938 to 28 August 1941 : Secretary of Finance under the Quezon Administration 
November 18, 1941 : elected as senator and later became the Senate president. During that time, he was also a reserve Major in the Philippine Army, a liaison officer and aide-to-camp to General Douglas MacArthur, then later promoted to Colonel and then Brigadier General.

During World War II, he, like Jose Laurel, was marked as collaborators even if he secretly supported the guerilla movement. After liberation, he ran for presidency where he had President Sergio Osmeña (Nacionalista Party) and Hilario Moncado (Partido Modernista) as adversaries.
He won and on 4 July 1946, Philippine's Independence was gained and Manuel became the first president of the Third Republic of the Philippines


During his term as president, he ratified the Bell Trade Act, included the Parity Amendment in the Constitution and signed the 1947 Military Bases Agreement. It was during his term the government was damaged by graft and corruption which caused distrust from the people. Furthermore, abuse from the military and police added to the existing problems with the left-wing Huks, the members of the HukBaLaHap (Hukbo ng Bayan Laban sa Hapon). Manuel Roxas attempted to crush these Huks but only created widespread anger among the peasants.
On 15 April 1948, while giving a speech at the Clark Air Force Base, Manuel Roxas had a heart attack. He died at the age of 56. He was succeeded by his vice president, Elpidio Quirino.

Cabinet and Judicial Appointments 1946-1948

The Commonwealth of the Philippines became the Republic of the Philippines on 4 July 1946. On that date, the Secretary of Foreign Affairs became the first in the order of presence among the cabinet.