This study aimed to explore the spiritual pain concept in the Iranian-Islamic context using a hybrid research model during 2020–2021. During the first phase, international and Iranian-Islamic literature was systematically searched and reviewed. During the second phase, the researchers referred to oncology wards, palliative care centers, and intensive care units and conducted unstructured interviews with 19 dying patients. In the third phase, attributes, and final analysis of spiritual pain was extracted from the first phase, and following the second phase, the definition of spiritual pain was finalized. The results showed that spiritual pain is a type of unique transcendental pain in the context of a continuum, rooted in human nature. At the one end of the continuum, there is the pain of deprivation from worldly pleasures (oneself, the family, and others). At the other end, there is the pain of breaking away from and striving to return to one’s origin (God). Exploring spiritual pain in the Iranian-Islamic context can help develop tools and clinical guidelines and plan for the presence of specialists at the bedside to relieve this pain.