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Introduction Depression is one of the most incapacitating psychiatric diseases that disturb life of millions of people round the globe. Its major causes include stressful life events, bereavement, social abuses or certain biological and genetic factors with complex causal mechanisms. Higher salivary cortisol levels for a long period lead to dyslipidemias which increase body mass index (BMI), elevate adiposity and waist-to-hip ratio (WHR). Such individuals with high quartiles of BMI have considerably higher risk of major depressive disorder. The aim of this study was to establish a correlation between major depression, BMI and salivary cortisol. Methods This cross-sectional analysis was accomplished in the Physiology Department, Sheikh Zayed Federal Postgraduate Medical Institute, Lahore as well as in Punjab Institute of Mental Health, Lahore, Pakistan, over a period of six months. A total of 60 participants aged between 18 and 60 years were included in this study; they were divided equally into two groups as normal healthy individuals with no physical or mental illness and severely depressed groups. The patients were categorized as cases of severe depression on outdoor clinical assessment and further confirmed by ICD-10. Patient's BMI was estimated by measuring height in meters (m) and weight in kilograms (kg), and then dividing weight with square height. Early morning saliva samples were collected. Estimation of cortisol levels in saliva was done through ELISA. SPSS version 20.0 (IBM Corp., Armonk, NY) was used to analyze the data and p ≤ 0.05 was considered statistically significant. Results The mean BMI in normal healthy group was 22.02 ± 4.21, while the mean BMI in severely depressive group was 24.64 ± 3.58. The difference was statistically significant (p = 0.012). The mean salivary cortisol level was significantly raised in patients with major depression (2.23 ± 1.69 nmol/L) in contrast to healthy normal individuals (1.46 ± 0.91 nmol/L), with p-value = 0.031. Conclusion BMI and depression has a very noteworthy correlation and there is a remarkable link between raised salivary cortisol, greater BMI and development of major depression.