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Background: Substance use is becoming a global health problem that concerns health professionals and decision makers. Studies showed that teens are at higher risk for substance use. Purpose: the purpose of this study was to examine the prediction power of the selected sociodemographic and psychological factors on substance use among high school students in Jordan. Specific aims were; 1) to explore substance use among high school students in Jordan, and 2) to examine the prediction power of sociodemographic and psychological factors on substance use among high school students in Jordan. Methods: This is a predictive cross-sectional study where data was collected using self-administered questionnaires from a convenience sample of 1497 high school students in the central district of Jordan. Results: Students who reported that they have never used stimulant agent were 91.5%, tranquilizer sedative 87.2%, hypnotic agent 85.8% and antidepressant agent 94.5%, while those never used nicotine were 81.7%. Coping efficacy (crude OR = 1.07, CI 95% = 1.03 – 1.12), psychological distress (crude OR = 1.07, CI 95% = 1.03 – 1.11), and perceived social support from family (crude OR = 1.20, CI 95% = 0.95 – 1.24) were significantly associated with substance use. While perceived social support from friends was not. Conclusion: High school students are at risk for the use of various forms of substances and mainly the over counter ones. Legitimate rules of screening and using substance prevention programs at high schools considering the psychological factors is a priority for school health professionals and policy makers.