Substance use is a growing problem in Nigeria. The present study extended recent work documenting the importance of parenting as protective against substance use in Nigerian youth by testing a model linking parenting, additional protective factors and polysubstance use. Public school students (N = 1607; 56% female; M age = 14.88; SD = .44 years) living in the greater Lagos region participated in school-based data collection. Lifetime polysubstance use, defined as use of two or more substances including alcohol or illicit drugs, or misuse of over-the-counter medications, was reported by 5.2% of the sample. Structural equation modelling that accounted for adolescent age and sex on all constructs revealed good model fit. Positive parenting (support and solicitation) was significantly associated with higher perceived harmfulness of substance use, religiosity and positive relationships at school. Positive school relationships were associated with a decreased likelihood of polysubstance use. Multiple group analysis revealed no overall sex differences in the model paths. Strengthening parent-adolescent relationships may have a cascading effect on protective factors and subsequent substance use, and should be included in youth substance use prevention programmes.