Since the late 1990s, deaths related to drug and alcohol abuse and suicide have increased substantially in the United States. Religious ecology is an important community attribute with theoretical links to these “deaths of despair.” This study uses spatial autoregressive models to explore the relationship between religious ecology and deaths of despair, analyzing 2,992 US counties. Analyses focus on the effects of four American religious traditions (Mainline Protestant, Evangelical Protestant, Black Protestant, and Catholic), and how religious ecological effects interact with structural community disadvantage. Mainline Protestantism is protective in communities of low to medium disadvantage, while Black Protestantism is protective at high levels of disadvantage. Catholicism is positively associated with death rate at high levels of disadvantage. These denominational differences are likely linked to social processes of organizational support and norms about alcohol, which vary in efficacy and salience by community disadvantage. Overall, findings highlight the importance of religious ecology to understanding community health and mortality, as well as nuance in where and how religious ecology matters.