A significant body of research has identified the deleterious effects of stress on psychological well-being (e.g., Tataro, Luecken, & Gunn, 2004). Religiosity and religious coping have been identified as variables that may impact a person’s experience with stress (Ano & Vasconcelles, 2005). Aukst-Margetic and Margetic (2005) suggest that the connection between stress, religious variables, and well-being can be understood through the frame of psychoimmunodocrinological research, which examines the relationship between neurohormonal functioning (e.g., cortisol level) with psychological factors that may impact health. The purpose of this study was to investigate whether acute stress reactivity, as measured by changes in cortisol levels in response to a laboratory stressor, is related to religiosity, religious coping, and psychological well-being such as depression and anxiety. Another purpose of this study was to attempt to replicate and extend Tataro, Luecken, & Gunn (2005), which found evidence that higher religiosity and composite religiosity/spirituality was associated with lower cortisol level after exposure to acute stress. Results indicated that cortisol level was not significantly related to gender, self-rated religiousness, spirituality, frequency of prayer, or forgiveness. In addition, cortisol reactivity was not significantly related to measures of psychological well-being, although negative religious coping significantly predicted depression, and state and trait forms of anxiety. Limitations, practical implications, as well suggestions for future research are discussed.