Objective: We evaluated how applying post-stratification sampling weights to National College Health Assessment II (NCHA-II) data affects estimates of substance use prevalence and tests of medical and recreational marijuana legalization (MML and RML) effects. Participants/Methods: We constructed weights for Fall 2015 and Spring 2016 surveys (n = 90,503) using population information on U.S. undergraduates’ gender and race/ethnicity and three institutional characteristics (region, city population, public/private). We estimated substance use prevalence (e.g., e-cigarettes, prescription opioid misuse) and compared 30-day marijuana use rates in states with RML, MML, or neither policy. Results: When unweighted versus weighted data were used, prevalence estimates did not differ appreciably; conclusions from logistic regressions were similar (weighted 30-day marijuana use rates among undergraduates in RML, MML, and non-ML states were 30.0%, 20.3%, and 16.3%, respectively) but effect sizes differed. Conclusions: The value of using weighted NCHA-II data depends on the analysis and the precision required for the research questions.