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Depression is a global mental health crisis, and the rapid-acting antidepressant scopolamine (Scop) is limited by systemic administration drawbacks. This study developed a scopolamine-loaded bilayer dissolving microneedle (Scop-DMN) system for transdermal delivery and evaluated its antidepressant efficacy in a chronic restraint stress (CRS)-induced mouse model. Bilayer DMNs were fabricated via sequential centrifugal molding, with a polyvinyl alcohol (PVA) backing layer and a dextran‑sodium hyaluronate drug-loaded tip matrix. Physicochemical properties, biocompatibility, and in vivo therapeutic effects were systematically characterized. Scop-DMNs showed uniform conical morphology, high drug loading homogeneity, and complete dissolution within 2 min in porcine skin. In C57BL/6 J mice, Scop-DMNs significantly ameliorated CRS-induced depressive-like behaviors in open field, sucrose splash tests, and tail suspension tests 24 h post-administration, outperforming conventional intraperitoneal scopolamine. Mechanistically, Scop-DMNs robustly activated the brain-derived neurotrophic factor / mammalian target of rapamycin (BDNF/mTOR) pathway and upregulated synaptic proteins (postsynaptic density protein 95 (PSD95), Synapsin I (SynI)) in the medial prefrontal cortex (mPFC), reversing stress-induced neurotrophic and synaptic deficits. This Scop-DMN system provides a safe, minimally invasive, and effective transdermal platform for scopolamine delivery, offering a promising clinical strategy for rapid management of acute depressive episodes.