Curcumin (CUR) exhibits a definite curative effect in the treatment of depression. To identify potential antidepressant targets and mechanisms of action of CUR. This study used network pharmacology to explore the signaling pathways and CUR-related targets in depression. C57BL/6 J mice (male,12-14 weeks old) were randomly divided into four groups (n = 8): saline-treated (control mice), lipopolysaccharide (LPS, 2 mg/kg/day, intraperitoneally), LPS + CUR (50 mg/kg/day, intragastrically), and LPS + CUR + LY294002 (7.5 mg/kg/day, intraperitoneally). After 1 week, behavioral tests were performed. Then, neuronal damage in the prefrontal cortex of mice was evaluated by hematoxylin-eosin (HE) staining. We uncovered the main active mechanism of CUR against depression using Western blotting and enzyme-linked immunosorbent assay (ELISA). Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways showed that the most significantly enriched pathway in CUR against depression was the PI3K-Akt pathway. Moreover, 52 targets were significantly correlated with the PI3K-Akt signaling pathway and CUR-related targets. In addition, among the top 50 targets ranked by degree in the protein-protein interaction (PPI) network, there were 23 targets involved in the 52 intersection targets. Administration of LPS alone extended immobility time in the open field test (OFT) and tail suspension test (TST) and decreased sucrose consumption in the sucrose preference test (SPT). Pretreatment with CUR relieved LPS-induced changes in the behavioral tests, activity of the PI3K-Akt signaling pathway, neuronal damage in the prefrontal cortex (PFC), and inflammatory response. Moreover, inhibition of the PI3K-Akt signaling pathway by LY294002 blocked the therapeutic effects of CUR. Our study indicates that CUR may be an effective antidepressant agent in an LPS-induced mouse model, partly because of its anti-inflammatory action through the PI3K-Akt signaling pathway.