To investigate the effects and mechanisms of deer antler total polypeptides (VAP-T) and its active component Y (VAP-Y) in treating depression in CUMS mice.VAP-T improved depression-like behavior in CUMS mice, reduced microglial activation, and tissue inflammation. VAP-Y showed better improvement in depression-like behavior in CUMS mice compared to VAP-T, significantly inhibiting microglial activation and tissue inflammation. Chromatographic analysis of VAP-Y revealed that short peptides had good binding activity with TREM2. VAP-T and VAP-Y have significant improvement effects on depression-like behavior in CUMS mice, which is related to the inhibition of TREM2-mediated microglial activation. VAP-Y has better activity than the total polypeptides and is a polypeptide with potential for treating depression.