The study aimed to assess the prevalence of cannabis and amphetamine use and socio-ecological proximal and distal factors among adolescents in six Pacific Island countries. We analyzed cross-sectional survey data from 9,849 adolescents (mean age 14.2 years, SD = 1.2) from Cook Islands, Kiribati, Samoa, Solomon Islands, Tonga and Tuvalu that participated in the “Global School-Based Student Health Survey (GSHS)” in 2011–2013. The prevalence of past-month cannabis use was 15.5%, and lifetime amphetamine use was 14.5%, with the highest prevalence in Samoa, 37.1% and 34.6%, respectively. In adjusted mixed-effects logistic regression analysis male gender, personal attributes (anxiety, loneliness, current tobacco use, current alcohol use and school truancy) and environmental stressors (having been in a physical fight, been physically attacked, sustained an injury, hunger and being bullied) were associated with past-month cannabis and/or lifetime amphetamine use. Parental substance use was positively and parental involvement negatively associated with past-month cannabis and/or lifetime amphetamine use. Measures to prevent and control cannabis and amphetamine use in this adolescent population should include personal attributes, environmental stressors and parental support. © 2018, National Academy of Psychology (NAOP) India.