To investigate the effect of Morinda officinalis How. (MO) extract on social cognitive ability in male depressed mice and to elucidate its underlying molecular mechanisms and potential targets, different doses of MO were administered to intervene in chronic restraint stress (CRS) mice. Mice social behavior was measured and the expression levels of proteins, such as tyrosine hydroxylase (TH), melanoma-associated antigen D1 (MAGE-D1), phosphorylated phosphatidylinositol-3-hydroxykinase (p-PI3K), and phosphorylated protein kinase B (p-PKB/Akt), were determined. Additionally, molecular docking was performed to analyze the interaction between MAGE-D1 and the key active components of MO. The results demonstrated that MO markedly improved the social cognitive ability of male depressed mice. Compared to the CRS group, treatment with medium-dose MO markedly increased TH-positive expression in the cornu ammonis 1 (CA1), cornu ammonis 3 (CA3), dentate gyrus (DG) hilus, and midbrain, with positive cell counts rising by 47.52%, 121.18%, 26.12%, and 77.85%, respectively (P<0.01). The positive expression of MAGE-D1 in the CA1 and CA3 was also significantly enhanced, with positive cell counts increasing by 72.06% and 52.15%, respectively (P<0.001). Furthermore, the expression levels of p-PI3K and p-Akt in brain tissue were upregulated by 2.34- and 4.48-fold, respectively (P<0.001). Molecular docking revealed a strong binding affinity between the active components of MO and MAGE-D1. In conclusion, 50 mg•kg-1•d-1 MO may improve social cognitive ability in male depressed mice by upregulating the PI3K/Akt signaling pathway and increasing the expression of TH and MAGE-D1. MAGE-D1 was identified as a potential target for antidepressant therapy. These findings provide a theoretical basis for the clinical prevention and treatment of male depression with traditional Chinese medicine while also offering a reference for the research and development of new antidepressants.