Background Major depressive disorder (MDD) is a prominent psychiatric disorder that significantly reduces living quality and increases the risk of suicide. Ghrelin influences the central nervous system (CNS) and impacts reward, inspiration, and signaling pathways in addition to acting as an appetite signal. This case-controlled comparative study focused on the association between serum ghrelin levels and MDD. The study was done during September 2021 and March 2022 on 25 people with MDD and 25 healthy controls. SCID-1 and the Ham-D 17 scales were used to evaluate the cases. The GHQ scale was used to evaluate the controls. The serum ghrelin levels of all samples were determined. The findings were presented, and statistically analyzed to perform an accurate assessment. Results There were 50 subjects: 25 cases of MDD and 25 healthy matched controls with non-statistically significant difference to cases as regard gender, marital status, residence, education, age, height, weight and body mass index (BMI). Total serum ghrelin levels among our cases showed a mean value of 4.152, while the controls showed markedly low values, with a mean value of 0.436, showing a statistically significant difference between both groups with p < 0.001. Furthermore, Post Hoc analysis by least significant difference showed a significant difference between mild-severe and moderate-severe groups, although there was no statistically significant difference between mild and moderate groups. Conclusions There was a significant indirect correlation between serum ghrelin level and severity of the illness. Further investigations via longitudinal studies and on larger samples are recommended to settle specific causal paths between the two variables.