Sexually transmitted infections pose a public health crisis globally and in low and middle-income countries, and substance use has been linked to an increased risk of engaging in risky sexual behaviors among youths. This work aims to explore the relationship between substance use and risky sexual behaviors among school-based youths in Liberia. An 86-question survey was developed to collect information about substance use and sexual behaviors. The survey was validated using qualitative data obtained from focus groups of Liberian youths. 400 students were sampled with a mean age of 18.15 ±2.14 years. Students who use alcohol were 2.4 times more likely to have multiple sexual partners (OR=2.38, CI= 1.06-5.32, p=0.035), 11 times more likely to engage in unwanted sexual activity (OR=10.86, CI=1.36-86.96, p=0.025); marijuana use increased the risk of multiple unintended pregnancies (OR=5.49, CI= 1.37-22.03, p=0.016); users of heroin had 4 times the odds of engaging in unwanted sexual activity (OR=4.18, CI= 1.07-16.37, p=0.039). Substance use increases the risk of engaging in risky sexual behaviors among youths in Liberia. Intervention programs that target individual, community, and societal level determinants are needed to tackle risky sexual behaviors in this population.