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 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. 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.