He was born in Quảng Bình Province, home to general Võ Nguyên Giáp and Ngô Đình Diệm, president of the Republic of Vietnam.

In 1944, he secretly returned to Vietnam and was made leader of the Communist Party committee branch in Quang Trach Phu, served as editor-in-chief of the Hong Lac Newspaper, built up the Trung Thuan Military Zone, trained the armed forces, and participated in the August Revolution.

In early 1967 (although he was offered the position in December 1966),[4] he was assigned Chief-in-Command of 559 Troop, replacing colonel Hoang Van Thai.

Dong Sy Nguyen was one of important persons in constructing the Ho Chi Minh trail during Vietnam War.

When he became commander of the Ho Chi Minh trail he converted it from an old low-key covert supply line into a modern strategic overt battlefield.

Much of his success stemmed from the fact that he converted most of his forces, which had previously used foot power, bicycles or elephants to carry loads, into vehicle transportation units.

He was assigned by Vietnamese prime minister Phan Văn Khải as the special envoy in supervision of Ho Chi Minh Highway.