Emerging evidence suggests that dysfunction of the visual cortex may be involved in major depressive disorder (MDD). However, the underlying mechanisms remain unclear. We previously established that combined magnetic stimulation system treatment (c-MSST) resulted in an antidepressant effect in mice. In the present study, we found that V1-targeted c-MSST induced significant antidepressant effects in chronic unpredictable mild stress (CUMS)- and lipopolysaccharide (LPS)-treated mice. Proteomic screening investigation and repeatable validation revealed that expression of the V1 neuronal ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein A-1 (ApoA1) was downregulated in CUMS mice, an effect that was normalized by c-MSST. Neuron-specific knockdown of ABCA1 in V1 blocked c-MSST's antidepressant effects. Mechanistically, CUMS reduced dendritic spine density and long-term plasticity in V1, and these deficits were reversed by c-MSST. V1-targeted c-MSST was found to induce rapid antidepressant effects that are mediated by alterations in synaptic plasticity via the ABCA1/ApoA1 signaling pathway in V1.© 2022 The Authors.