The aim of this study was to assess the prevalence of cannabis and amphetamine use and associated factors among adolescents in nine African countries. We analyzed cross-sectional data from 25,372 adolescents (mean age 14.3 years, SD = 1.6) from nine African countries that participated in the Global School-Based Student Health Survey (GSHS) in 2009-2013. Information was collected with a self-administered structured questionnaire. Overall, past-month cannabis use was 4.1% and lifetime amphetamine use was 5.1% among students. In multivariable unconditional regression analysis older age, personal attributes (suicidal ideation, current smoking, school truancy, and having had two or more sexual partners), smoking status of the father and/or mother, and environmental stressors (having experienced hunger, been bullied, having been in a physical fight and having been attacked) were associated with both past-month cannabis and lifetime amphetamine use. Measures to prevent and control cannabis and amphetamine use should include personal attributes (suicidal ideation, school truancy, and HIV sexual risk behavior) and environmental stressors (food insecurity and violence).