Oxytocin alleviates liver fibrosis via hepatic macrophages. This study reveals that oxytocin reverses liver fibrosis by promoting a phenotypic switch in hepatic macrophages from Ly6C high to Ly6C low expression. Single-cell sequencing identified oxytocin target cells, and the mechanism involves oxytocin-induced calcium influx activating the orphan nuclear receptor Nr4a1, which controls macrophage phenotypic switching. Oxytocin treatment reduced liver fibrosis in mouse models, with effects mediated by hepatic macrophages. The study highlights a novel pathway by which oxytocin regulates macrophage phenotype and suggests potential clinical applications of oxytocin and its analogs in liver fibrosis treatment. The findings establish hepatic macrophages as a central hub in oxytocin-mediated liver fibrosis alleviation. The study also reveals that oxytocin signaling system activates the MAPK pathway and promotes CREB transcription factor binding to the Nr4a1 promoter region, facilitating the phenotypic switch. The results suggest that oxytocin has dual roles in liver fibrosis progression and alleviation by regulating macrophage subpopulations. The study provides new insights into the therapeutic potential of oxytocin in liver fibrosis.Oxytocin alleviates liver fibrosis via hepatic macrophages. This study reveals that oxytocin reverses liver fibrosis by promoting a phenotypic switch in hepatic macrophages from Ly6C high to Ly6C low expression. Single-cell sequencing identified oxytocin target cells, and the mechanism involves oxytocin-induced calcium influx activating the orphan nuclear receptor Nr4a1, which controls macrophage phenotypic switching. Oxytocin treatment reduced liver fibrosis in mouse models, with effects mediated by hepatic macrophages. The study highlights a novel pathway by which oxytocin regulates macrophage phenotype and suggests potential clinical applications of oxytocin and its analogs in liver fibrosis treatment. The findings establish hepatic macrophages as a central hub in oxytocin-mediated liver fibrosis alleviation. The study also reveals that oxytocin signaling system activates the MAPK pathway and promotes CREB transcription factor binding to the Nr4a1 promoter region, facilitating the phenotypic switch. The results suggest that oxytocin has dual roles in liver fibrosis progression and alleviation by regulating macrophage subpopulations. The study provides new insights into the therapeutic potential of oxytocin in liver fibrosis.