In 1953, the Oklahoma Legislature created the agency to enforce drug laws. Designated the Division of Narcotics Enforcement, the agency operated under the Attorney General of Oklahoma for the next decade. In 1964, the Division of Narcotics Enforcement was abolished and created under the name of the Oklahoma Bureau of Narcotics. The new bureau was placed under the direct command of the Governor of Oklahoma.

In the late 1960s, narcotics operations and drug-related crimes accelerated. Despite a merger into the Oklahoma State Bureau of Investigation (OSBI) in 1968, only one full-time narcotics agent was employed by the state. Recognizing this problem, the Legislature granted OSBI funds to establish a full-time narcotics unit, but by the early 1970s the unit had been proven a failure. In response, the Legislature passed the Uniform Control Dangerous Substances Act of 1971. The Act established the Commissioner of Narcotics and Dangerous Drugs Control under the direction of the Attorney General. The Commissioner was responsible for the state's general interest in controlled drugs but actual enforcement of the Controlled Substances Act was left to the OSBI.

It soon became apparent that this arrangement failed to respond to controlling the surging drug trade. Therefore, in 1975, the Oklahoma Bureau of Narcotics was reconstituted, this time more adequately staffed and equipped, and given the necessary autonomy to operate in the war on drugs. The Bureau has original jurisdiction statewide on all violations of the Uniform Control Dangerous Substances Act as well as crimes of human trafficking.