Background:Illicit drug use results in considerable global morbidity, but there is little data on its trends and factors associated with it in sub-Saharan Africa. We consider these questions using national data from South Africa for 2002-2017.Methods:We analysed data among individuals aged 15 years or older from five national population-based household surveys in South Africa (2002-2017;n=89,113). Recent drug use was defined as the last three-months use of illicit drugs, i.e., any use of cannabis, cocaine, amphetamine, inhalants, sedatives, hallucinogens, opioids, and/or other illicit drugs. Time trends in recent drug use were assessed using logistic regression. Multivariable logistic regression assessed the association between recent drug use and socio-demographic factors and between drug use and sexual risk behaviours, HIV-related and other well-being variables. Results: The prevalence of recent drug use increased from 1·5% to 10·0% from 2002-2017, driven by increases in cannabis use (1·5% to 7·8%) and use of opioids (0·01% to 1·6%), cocaine (0·02% to 1·8%), or amphetamines (0·1% to 1·5%). In adjusted analyses, male gender, younger age, living in urban areas, mixed-ancestry or white ethnicity (compared to black-African), and unemployment were positively associated with recent drug use. Recent drug use was associated with: multiple sexual partners (adjusted odds ratio [aOR] 2·13, 95% confidence interval [CI]: 1·80-2·51); sexual debut before 15 years old (aOR 1·70, 95%CI: 1·29-2·23); hazardous/harmful alcohol use (aOR 2·50, 95%CI: 2·14-2·93) or alcohol dependence (aOR 3·33, 95%CI 2·92-3·80); ever experiencing intimate partner violence (aOR 1·56, 95%CI 1·12-2·17); psychological distress (aOR 1·53, 95%CI: 1·28-1·82); and lower chance of ever testing for HIV (aOR 0·89, 95%CI 0·80-1·00). Recent drug use was not associated with HIV positivity, condom use or being on antiretroviral therapy. Conclusion:Illicit drug use has increased substantially in South Africa and is associated with numerous socio-demographic characteristics, higher sexual risk behaviours and other well-being variables