This study was carried out to determine the relationship between the spiritual orientation and psychological well-being levels of inpatients diagnosed with COVID-19 and the factors affecting the psychological well-being of patients. This cross-sectional study was conducted with 136 patients diagnosed with COVID-19 who were hospitalized in the COVID-19 clinics of a state hospital between May and July 2021 and volunteered to participate in the study. To collect the study data, the Personal Information Form, Spiritual Orientation Scale (SOS) and Psychological Well-Being Scale (PWBS) were used. There was a positive correlation between the mean scores obtained from the overall SOS and PWBS ( r = .335, p < .001). Of the participants, those who were women, who were over 65-year-old patients, who were hospitalized for 8–14 days and who had chronic diseases had lower levels of psychological well-being. The inpatients with a diagnosis of COVID-19 had high levels of spirituality and psychological well-being. It was found that there is a relationship between the spiritual orientation and psychological well-being of inpatients hospitalized with the diagnosis of COVID-19. The fact that nurses take spirituality into account while providing care to patients diagnosed with COVID-19 may be effective in protecting their patients' mental health.