The early origins of phenazepam are hazy, but it is likely that the first synthesis occurred in the USSR in the mid-1970s, with the earliest mentions of it in Soviet medical literature coming from 1978. It was originally intended for use in treating psychological problems, but the discovery of its anti-convulsant properties led to it being investigated as a possible epilepsy treatment.

It was not until the 2000s that the first reports of phenazepam being used recreationally (or at least outside of a prescription setting) emerged in Western Europe. After a swathe of overdoses, including being linked to several fatalities, and the wide availability of the substance on the internet, the UK government moved to ban the importation of phenazepam in July 2011. It was added to the list of controlled substances under the Misuse of Drugs Act 1971 in 2012. However, it is still manufactured in the Russian Federation, where it is available on prescription and (by some accounts) without a prescription in certain pharmacies. It has appeared as a cutting agent, notably in heroin during the shortage of 2010. As a result, seizures of phenazepam still occasionally take place in the UK.