Sexual minority youth are at an increased risk for experiencing negative health outcomes, such as substance use and suicide. The goal of this study is to examine the role of sexual orientation and negative life events (i.e., bullying, forced sex, and intimate partner violence) in predicting these outcomes. Participants include 15,612 youth who participated in the Youth Risk Behavior Survey (YRBS), a nationally representative dataset of youth within the United States. A series of logistic regression models were used to estimate the main effects of sexual minority status and adverse life events on substance use and suicide. Path analyses were carried out to examine potential mediating effects of adverse life events. Findings indicate that sexual minority youth who report being bullied or who have experienced forced sex are more likely to use tobacco, alcohol, or marijuana. Both unsure and bisexual youth who report experiencing intimate partner violence are also more likely to use these substances. Finally, sexual minority youth who reported bullying and forced sex are more likely to report suicidality. Path analyses revealed indirect effects of sexual minority status on substance use and suicidality, partially mediated by adverse life experiences. Path analyses also revealed that sexual minority status had an indirect effect on substance use and suicidality associations with negative life events. These findings highlight an ongoing risk for these students, with a need for trauma-informed prevention and intervention for this population.