COVID-19 patients in self-isolation tended to be ignored and marginalized. This marginalization then results in fear, anxiety, depression, stress, trauma, and even suicidal tendency. During self-isolation, patients are only treated medically but their psychological and spiritual aspects are often abandoned. Hence, a more holistic approach is necessary to treat COVID-19 patients while they are in self-isolation. The present study aims to explain the self-isolation model in Muhammadiyah COVID-19 Pesantren in Indonesia as a comprehensive model with holistic, religious, spiritual, and psychological approaches. This research is a qualitative research. The research involved fifty respondents comprising founding spiritual figures of the Muhammadiyah COVID-19 Pesantrens, doctors and medical staff, psychologists, and COVID-19 survivors. The data were collected through observation, documentation, and interviews. Data analysis was conducted through data display, reduction, categorization, and interpretation. The research findings show that the Muhammadiyah COVID-19 Pesantren integrates the Islamic educational aspect and COVID-19 hospital concepts. The treatment through the three approaches resulted in the increased health of the COVID-19 patients. It is expected that the combination of spiritual, psychological, and medical approaches during the COVID-19 pandemic can be adapted to mitigate other diseases, such as TBC, HIV, or similar pandemics post COVID-19.