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Duterte placed the Philippines' illegal drugs problem at the forefront of his presidential campaign, warning the Philippines was at risk of becoming a narco-state. Upon entering office, Duterte began a nationwide crackdown against illegal drugs. At the forefront of the campaign's operations was Oplan Tokhang, which involved policemen knocking on the doors of suspected drug users and inviting them to surrender. Among Duterte's early actions included naming three Chinese nationals as alleged drug lords in the Philippines, calling for assistance from the New Peoples Army to join the crackdown, and publicly naming 150 public officials allegedly involved in the drug trade.

Concerns arose worldwide due to the rising death toll during police operations, and drug suspects reportedly fighting back ("nanlaban") was a common alibi of several policemen involved. At the height of the drug crackdown in his early presidency, Duterte urged the policemen to kill drug addicts, promising to pardon them for performing their duties; Duterte's call prompted thousands to surrender, and observers noted this assurance may have emboldened the police to allegedly execute suspects and plant evidence on them. In August 2016, opposition Senator Leila de Lima launched a probe into extrajudicial killings, focusing on cases that took place during Duterte's tenure as mayor of Davao City. De Lima presented as witness an alleged member of Davao City-based vigilante group Davao Death Squad, Edgar Matobato, who testified that Duterte was involved in extrajudicial killings in the city. Duterte dismissed the claims as a lie, and the Senate probe was terminated on October 13, 2016, for lack of evidence. Shortly after, Duterte implicated De Lima in the illegal drug trade during her tenure as Justice Secretary under the Aquino III administration. Though De Lima denied the claims, she was later imprisoned in February 2017 due to the drug charges. Two months later, Matobato's lawyer, Jude Josue Sabio, filed charges for crimes against humanity with the International Criminal Court against Duterte and 11 other officials.

Responding to public clamor, in October 2017, Duterte designated the Philippine Drug Enforcement Agency to lead anti-drug operations and temporarily barred the police from joining the raids. Through an executive order he issued in October 2018, Duterte instituted a more balanced approach to the drug problem by establishing the Philippine Anti-Illegal Drugs Strategy, which ordered all government departments and state universities and colleges to implement their own strategies in tackling the country's illegal drug trade; the order also urged local government units, non-government organizations, and private institutions to support and implement the Strategy.

Duterte campaigned to eliminate illegal drugs in the country within three to six months, but later acknowledged he miscalculated the severity of the problem as he based his approach to that of Davao City during his tenure as the city's mayor. Stating it would take him his entire term to eradicate it, he cited the difficulty in border control due to the country's fragmented geography and lamented that several government officials and law enforcers were involved in drug trafficking. Before leaving office, he implored president-elect Bongbong Marcos to continue tackling the illegal drug problem, but declined an appointment offer as Marcos' drug czar, expressing a desire to retire. By the end of Duterte's term, the number of drug suspects killed since Duterte took office was officially tallied by the government as 6,252; human rights groups, however, claim drug casualties reached as high as 12,000 to 30,000.

Various international publications and media companies had claimed that Duterte's anti-drugs campaign was a war against the poor due to the abject poverty of those arrested or killed. On June 19, 2018, 38 United Nations member states released a collective statement through the United Nations Human Rights Council, calling on the Philippines and Duterte to end the killings in the war on drugs and cooperate in investigating human rights abuses. Though many human rights note that Duterte's war on drugs was a stain on his legacy, the anti-narcotics drive received domestic approval during his term, and 58% of the country's barangays were declared by the government cleared of illegal drugs by February 2022.