People abuse substances like drugs, alcohol, and tobacco for different reasons, including pleasure, improved performance and vigilance, relief of depression, curbing hunger, and weight control. In this review, we sought to identify the determinants and prevention strategies that have been undertaken to minimize the issue of substance abuse. The systematic review was conducted following the Cochrane Library Guidelines and PRISMA checklist. We searched six online databases to identify studies from January 2000 to July 2017. Only peer-reviewed studies published in the English language that had full text accessible were included. We reviewed 19 studies; only one was quasi-experimental and the majority were descriptive studies. The determinants of substance abuse identified include personal, faciliatory/promotor, environmental, and social factors. The prevention strategies identified use culturally appropriate and gender-sensitive treatments, and identify sources of strength in families, community, individual, and even spiritual. Substance abuse poses significant public health risks and therefore requires adequate interventions such as educating and informing individuals of the health risks associated with substance abuse and must be considered locally to promote the well-being of people. The OMJ is Published Bimonthly and Copyrighted 2020 by the OMSB.