By the late 1960s he was a general and the group's chief-of-staff. He was also a member of the Standing Committee of the Khmer Rouge's Central Committee ("Party Center") during its period in power. He became very powerful within the party, especially in the south-west zone. He was named by Pol Pot as leader of the national army of Democratic Kampuchea. He lost the lower part of one leg in fighting around 1970.
Ta Mok is believed to have orchestrated many massacres within the zone he controlled from 1973, beginning before the final, complete seizure of power by the Khmer Rouge on April 17, 1975. It is believed that he directed the massive purges that characterised the short-lived Democratic Kampuchea (1975–1979), earning him the nickname Butcher.
After the regime was overthrown in 1979, Ta Mok remained a powerful figure, controlling the northern area of the Khmer Rouge's remaining territory from his base at Anlong Veng. It is estimated that some 3,000 to 6,000 combatants remained loyal to Pol Pot and were directed by Ta Mok.
In 1997, following a split in the party, Ta Mok seized control of one faction, naming himself supreme commander. Pol Pot then fled the Khmer Rouge's northern stronghold, but was later arrested by Ta Mok and sentenced to lifelong house arrest. In April 1998, following a new government attack, Ta Mok fled into the forest, taking Pol Pot with him. A few days later, on 15 April 1998, Pol Pot died, reportedly of a heart attack, in his custody.
In 1998, following several key defections, Ta Mok was forced to flee to Anlong Veng. On 6 March 1999, the general was captured by the Cambodian army near the Thai border and brought to Phnom Penh, where he joined former comrade Khang Khek Leu ("Duch") at the Military Prosecution Department Detention Facility. Ta Mok was the last leading member of the Khmer Rouge to remain at large in Cambodia; other senior figures had died or already made immunity deals with the government of Hun Sen, including Nuon Chea, Khieu Samphan and Ieng Sary.
In prison his detention period was repeatedly extended without his being brought to trial. Under Cambodian law his trial should have begun within six months of his arrest. Initially charged with membership of an outlawed group and tax evasion, in February 2002 he was charged with crimes against humanity. In poor health, Ta Mok's only releases from solitary confinement were for hospital visits. On 21 July 2006, he died in a military hospital after falling into a coma. "He was an old man and died of natural causes, given his poor health and respiratory problems," military doctor Tuoth Nara told Reuters.