Urban women of color are at risk of experiencing intimate partner violence (IPV) and human immunodeficiency virus (HIV). Both IPV and HIV are individually associated with negative psychological outcomes and spirituality has sometimes been linked to positive outcomes in the context of these adversities. Guided by syndemic theory, 155 women who were exposed to recent IPV and/or were living with HIV were interviewed for the present study. Women were recruited from community organizations in the United States Midsouth, serving survivors of IPV or individuals living with HIV. Hierarchical multiple regression with interaction terms was used to examine associations between demographics, HIV status, IPV severity, spirituality, and mental health symptomology (an average score of depressive, anxiety, and posttraumatic stress symptoms). The moderating effect of spirituality on the association between adversity (i.e., HIV and IPV) and mental health symptomology was also examined. Results revealed that women who were both living with HIV and experiencing severe IPV had greater mental health symptomology. Findings also revealed that spirituality moderated the HIV interaction, such that among women living with HIV high spirituality was associated with greater mental health symptomology. However, among women not living with HIV, higher spirituality was associated with lower mental health symptomology. Results of an IPV by spirituality and three-way interaction were not significant. Findings contribute to the literature by highlighting how spirituality is differentially associated with mental health among women exposed to adversity, suggesting the need for future research on how components of spirituality may relate to mental health.