Background We aimed to investigate the relationship between the hippocampal shape deformations and the serum cortisol levels in first‐episode and drug‐naïve major depression disorder (MDD) patients. Methods Thirty first‐episode and drug‐naïve MDD patients and 40 healthy subjects were recruited. High‐resolution T1‐weighted imaging and morning blood samples for cortisol measurement were obtained from all MDD patients and healthy subjects. In the hippocampal shape analysis, we compared the hippocampal shape between MDD patients and healthy subjects and evaluated the linear correlation between hippocampal shape deformations and the serum cortisol levels in MDD patients and healthy subjects. Results MDD patients showed significant inward deformations predominantly in the cornu ammonis (CA) 1 and subiculum in bilateral hippocampi compared to healthy subjects (false discovery rate (FDR) corrected, P < .05). Furthermore, in MDD patients, a significant linear correlation between inward deformations and high cortisol levels were found predominantly in the CA1 and subiculum, extending into the CA2–3 (FDR‐corrected, P < .05), whereas no significant linear correlation was observed in healthy subjects. Conclusions The serum cortisol levels are therefore considered to be associated with hippocampal shape abnormalities in MDD.