This study aimed to examine the relationship between piety and serotonin levels using an interdisciplinary approach and a descriptive–analytical method. Qualitative data were collected through in-depth content analysis of the Qur’anic verses and narrations of the Imams (peace be upon them), alongside data from a systematic review of empirical neuroscience studies. Findings indicate that piety, as an existential shield, affects the serotonergic system through multiple mechanisms: reducing cortisol levels by avoiding sin, enhancing self-control via increased prefrontal cortex activity, promoting sustained spiritual and inner calm through activation of raphe nuclei serotonergic pathways, and strengthening positive social behaviors via the brain’s reward system. Analysis of specific verses, particularly Qur’an 13:28 and 8:29, and hadiths from sources such as Al-Kafi and Bihar al-Anwar shows that piety leads to “inner tranquility,” which from a neuroscientific perspective is associated with serotonergic balance. This research not only contributes to developing a scientific framework for understanding the psychological effects of religious teachings but also provides a foundation for designing integrated clinical psychotherapy protocols. The findings may foster a dialectical paradigm between science and religion, offering both theoretical and practical contributions to the advancement of health psychology grounded in Islamic indigenous teachings.