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Being an important Islamic concept, tawakkul is a fundamental and core value in the Islamic belief system. The present research intended to investigate the mediating role of tawakkul between religious orientation and depression. A purposive sample of (N = 350) Muslim adults with the age of 25 years and above (M = 31.92, SD = 8.72) was recruited in the study. A cross-sectional survey research design was used. Tawakkul Scale (Gondal et al., 2021), Urdu version of depression subscale of DASS-21 (Aslam, 2018), and Urdu version of Religious Orientation Scale (Khan, et al., 2016) were used in the present study. Results indicated that tawakkul had a negative relationship with depression and extrinsic social religious orientation. On the other hand, it had a positive relationship with intrinsic religious orientation and extrinsic personal religious orientation. The findings of the path model indicated that tawakkul mediated the relationships of intrinsic and extrinsic personal religious orientations with depression. Limitations, implications of the findings of the present study, and suggestions for future investigations have been reflected upon.