Natural disasters have increased exponentially in recent decades, imposing existential threats to humans. Yet, surprisingly little research has explored the role of religion and spirituality (R/S) and transcendence-related character strengths in post-disaster depression. Using data (N = 491) from victims of Category 5 Hurricane Michael, this study examined whether R/S factors and character strengths helped to buffer against post-disaster depressive symptoms. A hierarchical regression model revealed an inverse association of perceived spiritual support with depression, after adjusting for demographic and event-related factors; strength of faith and the use of prayer for coping were not significantly related with depression. Upon inclusion of character strengths into the model, those relationships changed dramatically. Hope and optimism negatively predicted depression, whereas strength of faith and prayer for coping did so positively. Follow-up moderation analyses found that victims reporting particularly high levels of R/S factors and particularly low levels of character strength experienced the most depressive symptoms. The findings suggest that the potential protection of R/S factors in disasters may actually be due to transcendence-related character strength factors.