Lesbian, gay, and bisexual (LGB) individuals report higher levels of alcohol and substance misuse than their heterosexual peers, and previous research has linked these increased rates to LGB-specific stressors, termed minority stress. However, not everyone experiencing minority stress reports increased rates of alcohol and substance misuse. Emotion regulation (ER), which plays a critical role in psychopathology generally, is postulated to modulate the link between minority stress and psychopathology. However, it remains largely unknown whether ER plays a role in linking instances of minority stress with substance and alcohol use outcomes. To address the gap, the current study assessed 305 LGB individuals’ instances of minority stress, ER, and substance and alcohol use outcomes. We assessed the role of ER in alcohol and substance misuse among LGB individuals using moderated logistic regression and exploratory machine learning analyses. Moderated binary logistic regressions revealed that emotional non- acceptance moderated the relationship between minority stress and problematic substance use, such that those with poor ER were more likely to have problematic substance use. Additionally, deficits in goal-directed behavior moderated the relationship between minority stress and alcohol and substance use, but those with more deficits in goal-directed behavior had better outcomes. Exploratory machine learning analysis revealed multivariate patterns of additional facets of ER and psychiatric symptoms that are predictive of alcohol and substance use. These results highlight the important explanatory role that ER may have between instances of minority stress and substance and alcohol use in LGB individuals.