Theory and research indicate that experiences of sexual and gender minority (SGM) stress among Lesbian, Gay, Bisexual, Transgender, Queer, plus (LGBTQ+) individuals are related to a variety of negative health outcomes. Because positive romantic relationships promote better physical and mental health outcomes, understanding factors that contribute positively or negatively to relationship functioning is necessary to improve relationships and promote physical and mental health. As such, the primary goals of the present study were to conduct a meta-analysis on the association between SGM stress and (1) relationship functioning and (2) substance use, a well-established predictor of relationship functioning. We used multivariate meta-analysis with robust variance estimation to summarize the effects. Across 304 effects from 73 studies, we found a significant negative association between SGM stress and relationship functioning, r = −.13, 95% CI [−0.16, −0.10]. We also found significant positive associations between SGM stress and alcohol use r = .08, 95% CI [0.06, 0.11], and drug use r = .09, 95% CI [0.05, 0.13]. These small, but significant, relations are interpreted to indicate that SGM stress could erode relationship functioning and, in turn, weaken its potential protective effects against negative health outcomes, although longitudinal studies are needed.