Background: Tobacco smoking, alcohol use, and illicit drug use are significant health, psychological, and social problems among youth in Palestine. The aim of this study was to provide insight into the extent and the pattern of psychoactive substance use among schoolchildren in the West Bank in Palestine. A cross-sectional study in 16 schools was conducted in 2016. Eight hundred seventy-seven students of 10th grade were chosen randomly. Modified self-administrated questionnaire from Monitor the Future Study and European school survey project on alcohol and other drugs was used. Results: The most current substance used by schoolchildren was tobacco (40.6%), followed by alcohol (3.2%) and illicit drugs (2.0%). Around 59.7, 7.9, and 2.9% of the schoolchildren had tried, at least once in their lifetime, tobacco, alcohol, and illicit drugs, respectively. Moreover, 11.1% of them who had not yet tried a substance intends to smoke tobacco, 1.4% intends to drink alcohol, and 0.3% intends to try illicit drugs. Curiosity and experience was the most frequent motivation for using these substances. The mean age of initiation was 12 years for smoking and 14 years for drinking alcohol or using illicit drugs. Most of the illicit drug users (78.3%) had tried more than one illicit drug or more than one substance at the same time. Cannabis and synthetic cannabinoids followed by amphetamines were the most commonly used drugs. Around 78.8%, 37.6%, and 27.6% agreed that tobacco, alcohol, and illicit drugs, respectively, were easily accessible in their communities. Work was significantly associated with increased risk for substance use across various substances. Conclusion: Many factors had determined the danger of using psychoactive substances by Palestinian schoolchildren including the initiation age, the availability, the type of the substances used, and the frequency of the use, and using multiple substances at the same time. Curiosity and experience, peer pressure, families, and working were the most important motives. Health care professionals, clinicians, and ministries of education, health, and labor have key responsibilities in preventing substance use among youth and need to develop more effective prevention and cessation strategies. The Palestinian National Authority needs to make more efforts in smoking legislation regulating the age of access and smoking for youths and adults.