Emotion regulation deficits may link stigma to poor mental health, yet existing studies rely on self-reported stigma and do not consider contextual factors. In the present research, we examined associations among cultural stigma (i.e., objective devaluation of others' status), emotion regulation deficits, and poor mental health. In Study 1, we created an index of cultural stigma by asking members of the general public and stigma experts to indicate desired social distance towards 93 stigmatized attributes. In Study 2, emotion regulation deficits mediated the association between cultural stigma and adverse mental health outcomes, including depressive symptoms and alcohol use problems, among individuals endorsing diverse stigmatized identities. The indirect effect of cultural stigma, via emotion regulation, on these outcomes was stronger among those reporting more life stress. These findings highlight the adverse impact of cultural stigma on mental health and its role in potentiating stigmatized individuals' susceptibility to general life stress.