This study investigated the alterations in gray matter (GM) networks and their relationship with serum cortisol levels in first-episode, drug-naïve major depressive disorder (MDD) patients using source-based morphometry (SBM). Forty-two MDD patients and 39 controls were studied. MDD patients showed significantly higher serum cortisol levels. SBM analysis revealed two significantly different GM sources between groups: a prefrontal network and an insula-temporal network. Serum cortisol levels negatively correlated with the loading coefficients of the prefrontal network. Increased serum cortisol levels were associated with reductions in the prefrontal network in early-stage MDD, suggesting SBM as a useful approach for analyzing structural MRI data.