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Sickle cell trait (SCT) has long been considered a benign carrier condition; however, emerging evidence suggests that individuals with SCT may experience adverse health outcomes, both physical and mental. These findings challenge the conventional notion of SCT as clinically insignificant. Therefore, the present study aims to capture the physical and mental health of SCT individuals among scheduled caste (SC) and scheduled tribe (ST) populations of Odisha, India. This cross-sectional study was conducted in the hard-to-reach regions, primarily located in the mountainous terraces of Koraput district, Odisha. A total of 382 individuals (182 SCT individuals and 200 controls) of either sex, aged between 30 and 58, were recruited for the present study. SCT individuals were identified by screening through the sickle cell slide technique. Somatometric, physiological, and biochemical data were obtained using standard protocols and techniques. Beck’s Depression Inventory (BDI) tool was utilized to assess mental health. Hemoglobin, SpO₂, blood sugar, and pulse rate were significantly affected in SCT individuals. However, they were found to be protected against overweight, obesity, and hypertension. Most importantly, a significantly higher percentage of SCT individuals (17.03%) were depressed compared to the controls (4.5%) (p < 0.001). The present study found that physical health, mental health, and quality of life were affected among individuals with sickle cell trait. Therefore, it is important to recognize that being a carrier of the HbS gene is not always a benign condition.