He served in the French colonial administration, then took active part in Cambodian politics, was several times Prime Minister of Cambodia (1953, 1954–1955, 1958, 1961) as part of the Sangkum regime of Prince Norodom Sihanouk.

On 18 March 1970, when Norodom Sihanouk was deposed by Penn Nouth's successor Lon Nol, Penn Nouth joined the monarch in his exile and became prime minister in the GRUNK coalition.

His combined tenure as Prime Minister (5 years, 222 days), spanning seven non-consecutive terms, is the second-longest in Cambodian history after Hun Sen. On April 17, 1975, when the Khmer Rouge took power, he held the post of Prime Minister for the last time, until April 4, 1976, but without holding any power, Democratic Kampuchea being entirely controlled by Pol Pot's supporters.

He was subsequently placed under house arrest, like Norodom Sihanouk, until January 6, 1979, when, following the Vietnamese invasion, he returned to the People's Republic of China.

He emigrated to France, to Châtenay-Malabry where he obtained refugee status on March 6, 1981 and where he died on May 18, 1985, in his 80th year.