Decades of research have documented pervasive physical and mental health disparities among individuals holding a marginalized identity, including those who identify as lesbian, gay, bisexual, or queer (LGBQ). Heterosexism in the forms of harassment, rejection, and discrimination likely increases minority stress, which is theorized to contribute to documented health disparities. One group that may be particularly vulnerable to effects of heterosexist discrimination, harassment, and rejection is LGBQ college students, especially those who identify as first-generation and were raised in rural environments. The current study aimed to evaluate relationships between LGBQ discrimination, depression, and physical health outcomes at the bivariate level, as well as in mediation and moderated-mediation models. The current sample of LGBQ college students was drawn from an anonymous online survey focused on college student health behaviors. This sample endorsed high somatic symptom burden and levels of clinical depression. Results revealed statistically significant relationships between depression and physical health outcomes; however, heterosexist discrimination was not correlated with any study variable. Furthermore, depression was identified as a statistically significant mediator of the relationship between discrimination and somatic symptom burden, but not depression and self-rated health. First-generation status and rural upbringing were not statistically significant moderators of the mediation models. Results provide support for the health disparities experienced by LGBQ college students, however the mechanisms explaining the link between discrimination and poor physical health outcomes are still unclear for this population. Future research may evaluate other contextual factors that are more likely to influence college students’ daily lives (e.g., campus climate, support systems) as it relates to the minority stress model.