BACKGROUND psychoactive substance use (PSU) is a patterned use of a drug in which the user consumes the substance in amounts or methods which are harmful to themselves or others. Psychoactive substance use takes a considerable toll on financial status, academic achievement and health status of addicts. In Nigeria, PSU is on the increase, one of the most disturbing health-related problems and a leading cause of premature death among school aged population worldwide. We therefore, determined the knowledge of health effects and determinants of psychoactive substance use among secondary school students in Sokoto Metropolis, Nigeria. METHODS we conducted a cross-sectional study among 430 secondary school students that were selected using multistage sampling in Sokoto, Northwestern, Nigeria from April to May 2019. We collected data using a semi-structured, interviewer-administered questionnaire. We calculated proportions and adjusted odds ratios (OR) with 95% confidence intervals (CI) in a binary logistic regression model. RESULTS knowledge of health effects of PSU was good in 38.1% of the respondents with a mean score of 19.6 ± 10.0. The overall prevalence of PSU was high among current users (16.3%), male participants (78.6%) and those aged 17-years or more (68.6%). Independent predictors of current use of psychoactive substances were poor knowledge of health effects (aOR: 4.1, 95% CI: 1.7-10.0) and father´s use of psychoactive substances (aOR: 10.3, 95% CI= 1.9-57.1). CONCLUSIONS knowledge of health effects of psychoactive substances was generally poor among the participants with an associated high prevalence among current users. Poor knowledge of its health effects determines the use of psychoactive substances. We conducted awareness campaigns and health talk on health effects of PSU to secondary school students in the State. The Federal Ministry of Education should ensure that PSU-related topics are incorporated in the secondary school curriculum.