South Africa has a high rate of substance abuse among youths both in and out of school with East London in the Eastern Cape Province experiencing an increase in young people ages 20 years and below seeking treatment for substance abuse. The purpose of the study was to explore the knowledge of high school learners (grades 10 to 12) regarding substance use within their school premises. The objectives of the study were to assess knowledge of substance use within school premises among Buffalo Flats high school learners; assess the knowledge of learners regarding policies, rules, and regulations for preventing substance use within school premises; and determine learners' views regarding measures that should be taken to prevent substance use within school premises. A descriptive study design was used and a total of 146 learners participated by completing a self-administered questionnaire. The results revealed that learners were aware of substance use and users within their school premises. Alcohol, tobacco, and marijuana were identified as substances commonly used by learners at school with restrooms and sports grounds as main areas where substance use take place. There was limited knowledge of the South African policies, rules, and regulations in relation to substance use within school premises among learners. There is a need to create awareness among Buffalo Flats students about policies and regulations related to substance use, dangers of substances, and prevention of substance abuse.