The current study aimed to assess the strength of the relationship between neurodivergence (i.e., Autism, ADHD, learning disorders, or speech disorders) and substance use (i.e., marijuana and alcohol use) and the influence of these two variables on loneliness. This study also explored whether substance use moderates the relationship between neurodivergence and loneliness. Data for this study were derived from the 2022 National College Health Assessment (NCHA). Analyses included a chi-square test for independence to examine the association between neurodivergence and substance use, as well as a two-way between-groups analysis of variance to explore the combined effects of neurodivergence and substance use on loneliness. Results revealed a significant association between neurodivergence and substance use. Compared to neurotypicals, neurodivergent participants more often reported using alcohol or marijuana at least once in the 30 days prior to survey completion. Substance use was not shown to moderate the relationship between neurodivergence and loneliness. However, both neurodivergence and substance use were found to influence loneliness independently. Being neurodivergent was associated with higher levels of loneliness, as was having used a substance. Conclusions drawn from this study are important for the university to consider as the sample was comprised of WSU students. The results suggest that neurodivergent students are at heightened risk of substance use and potential misuse or abuse. Findings also revealed that both neurodivergence and substance use influence students’ levels of loneliness. This may be explained as neurodivergent and substance-using students similarly perceiving themselves as different from their campus community peers, which may result in social withdrawal and subsequent loneliness. It is the authors’ hope that this research will be used to incentivize the creation of targeted intervention efforts that will support neurodivergent students in accessing resources like support groups and substance abuse prevention programs.