Objectives <p>Focusing on the acute phase of major depressive disorder(MDD), this study aimed to systematically explore the specific correlations between core functional markers of the hypothalamic-pituitary-adrenal (HPA) axis and the seven factor dimensions of the 24-item Hamilton Depression Rating Scale (HAMD-24), moving beyond the conventional coarse-grained analytical framework that only associates HPA axis activity with the overall diagnostic status of depression to provide refined clinical evidence for elucidating the pathophysiological role of the HPA axis at the symptomatic dimensional level.</p> Methods <p>Ninety-nine outpatients with acute episodes of MDD and Eighty-seven healthy controls were selected. Serum samples were collected once in the morning from both groups to measure the serum cortisol levels. Multiple dimensions of clinical characteristics of the depressive group was assessed using the HAMD-24.</p> Results <p>Serum cortisol levels during acute depression episodes were significantly higher than those in the healthy control group. In the MDD group, serum cortisol levels were significantly positively correlated with the anxiety, cognitive impairment, diurnal variation and retardation factors and the total HAMD-24 score (ρ &gt; 0, <i>P</i> &lt; 0.05). It tended to be positively not significantly correlated with the despair factor (ρ &gt; 0, <i>P</i> &gt; 0.05), and tended to be negatively but not significantly correlated with the weight and sleep disturbance factors (ρ &lt; 0, <i>P</i> &gt; 0.05).</p> Conclusion <p>These findings refine HPA axis pathophysiology understanding in acute MDD, emphasizing symptom-specific associations over generalized depressive status links. Aberrant HPA axis activity emerges as a potential biological marker for acute MDD and a promising novel therapeutic target for antidepressant development.</p> Clinical trial number <p>Not applicable.</p>