Background: Heroin addiction remains a significant global health challenge with limited effective treatments. Vagus nerve stimulation (VNS) has shown promise in treating various neurological disorders, but its potential in addiction treatment is unexplored. Objective: To investigate the effects of VNS on heroin-induced conditioned place preference (CPP) and elucidate the underlying neurobiological mechanisms. Methods: We employed bilateral subphrenic vagotomy and VNS models in mice. Heroin-induced CPP was assessed following transcervical (nVNS) or transcutaneous auricular (taVNS) stimulation. Microglial activation in the nucleus accumbens (NAc) was evaluated using immunofluorescence and ELISA. The role of alpha 7 nicotinic acetylcholine receptors (alpha 7nAChRs) was investigated using the antagonist methyllycaconitine. Results: Both nVNS and taVNS significantly attenuated heroin-induced CPP. VNS reversed heroin-induced microglial activation in the NAc, reducing pro-inflammatory markers and cytokines while increasing antiinflammatory markers. These effects were mediated by alpha 7nAChRs, as antagonist administration abolished VNS efficacy. Notably, subphrenic vagotomy did not affect VNS efficacy, suggesting a primarily central mechanism of action. Conclusion: VNS inhibits heroin-induced CPP, likely through modulation of NAc microglia via alpha 7nAChRs. taVNS, while less effective than nVNS, offers a promising non-invasive approach to addiction treatment. These findings provide a rationale for further clinical investigation of VNS, particularly taVNS, as an adjunct therapy for heroin addiction. Brief abstract: Vagus nerve stimulation (VNS) attenuates heroin-induced conditioned place preference in mice by modulating microglial activation in the nucleus accumbens via alpha 7 nicotinic acetylcholine receptors. Both invasive and non-invasive VNS show efficacy, with the latter offering potential as a novel addiction treatment approach. These findings warrant further investigation of VNS in clinical settings for heroin addiction management.