The religious dimension of life represents an important source of human strength, meaning, and coping for many people. However, the religious life is not always “smooth and easy” and can be associated with weak personal adjustment, poorer psychological well-being, and lower satisfaction. Yet, besides the direct relationship between these variables, some researchers postulate the existence of an indirect association that has not been fully explained by various psychosocial mediators. The aim of the present study was to verify whether self-esteem could be a potential mediator between religious strain and life satisfaction. The sample consisted of 607 adult Christians (49.6% women) aged between 18 and 79. We used the Religious Comfort and Strain Scale, the Satisfaction with Life Scale, and the Rosenberg Self-Esteem Scale. Consistent with our hypotheses, life satisfaction positively correlated with religious comfort and was negatively associated with fear/guilt, negative emotions toward God, and negative social interactions surrounding religion. The same pattern of results was shown in the case of self-esteem. Moreover, the outcomes obtained from bootstrap sampling (5000) with a 95% confidence interval indicated a significant role of self-esteem as a mediator in all of the relationships between: (1) religious comfort and life satisfaction; (2) fear/guilt and life satisfaction; (3) negative emotions toward God and life satisfaction; and (4) negative social interactions surrounding religion and life satisfaction.