Background: Harmful alcohol and illicit drug use significantly contribute the burden of disease.Aim: This study aimed to assess the prevalence and correlates of hazardous, harmful or dependent alcohol (HHDA) use and drug use amongst persons 15 years and older in South Africa.Setting: Population-based survey.Method: In a national cross-sectional 2017 survey, 39 210 persons 15 years and older (Median = 34 years) responded to a questionnaire on substance and health variables. The prevalence of HHDA use was 10.3% and past 3-month drug use 8.6%.Results: In adjusted logistic regression analysis, men of middle age (25–34 year olds) with higher education, urban residence, drug use and psychological distress were positively associated and Indian or Asian and white population groups were negatively associated with HHDA. Women of middle age (25–34 year old) and mixed race, residing on rural farms and urban areas, with drug use and psychological distress were positively associated and older age (55 years and older) and Indians or Asians were negatively associated with HHDA. In adjusted logistic regression analysis, men, having Grade 8–11 education, mixed race, being unemployed, and the HHDA used were positively associated and middle and older age (25 years and older) and being a student or learner were negatively associated with past 3-month any drug use. Women, who were mixed race, Indians or Asians, with the HHDA use were positively associated and older age (45 years and older) were negatively associated with the past 3-month drug use.Conclusion: About one in 10 participants with several sociodemographic and health indicators was identified to be associated with HHDA and any drug use.