Researchers have examined perceived discrimination as a risk factor for depression among sexual minorities; however, the role of religion as a protective factor is under-investigated, especially among sexual minority youth. Drawing on a cross-sectional study investigating campus climate at a large public university in the U.S. midwest, we examined the role of affiliation with a gay-affirming denomination (i.e., endorsing same-sex marriage) as a moderating factor in the discrimination-depression relationship among self-identified sexual minority (n = 393) and heterosexual youth (n = 1,727). Using multivariate linear regression analysis, religious affiliation was found to moderate the discrimination-depression relationship among sexual minorities. Specifically, the results indicated that the harmful effects of discrimination among sexual minority youth affiliated with denominations that endorsed same-sex marriage were significantly less than those among peers who affiliated with denominations opposing same-sex marriage or who identified as secular. In contrast, religious affiliation with gay-affirming denominations did not moderate the discrimination-depression relationship among heterosexual participants. The findings suggest that, although religion and same-sex sexuality are often seen as incompatible topics, it is important when working with sexual minority clients for clinicians to assess religious affiliation, as it could be either a risk or a protective factor, depending on the religious group's stance toward same-sex sexuality. To promote the well-being of sexual minority youth affiliated with denominations opposed to same-sex marriage, the results suggest these faith communities may be encouraged to reconsider their position and/or identify ways to foster youth's resilience to interpersonal discrimination.