Objective Network pharmacology and molecular docking techniques were used to predict the potential mechanisms by which the active components of Piper nigrum( PN) regulate depressive-like behaviors in chronic restraint stress(CRS) mice. Methods The major chemical components and targets of PN were screened using the Traditional Chinese Medicine Systems Pharmacology database. Targets related to ferroptosis and depression were obtained from the Online Mendelian Inheritance in Man, GeneCards, and FerrDB databases. The intersecting targets were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Gnomes ( KEGG) pathway enrichment analyses, and molecular docking was performed to validate the binding capacities between the core targets and their corresponding active components. Finally, we established a CRS mouse model. Mice were treated with PN 75, 150, and 300 mg / kg for 4 weeks, followed by behavioral assessments and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to verify the expression of core genes. Results Nine active components were screened from PN, corresponding to 27 targets, and 8377 targets related to depression and 547 targets associated with ferroptosis were screened from the databases. The intersection of these three sets resulted in 25 target genes. KEGG enrichment analysis revealed that these core targets were predominantly enriched in signaling pathways, including cholinergic synapses, serotonergic synapses, and neuroactive ligand-receptor interactions. Molecular docking result showed that the main active components of PN had strong binding affinities for the targets CHRM2, SLC6A4, PTGS2,and SLC6A2. Behavioral assessments demonstrated that PN significantly increased the sucrose preference index(P<0. 01,P<0. 001), reduced immobility time in the tail suspension and forced swimming tests(P<0. 01,P<0. 001),and enhanced exploratory behavior in the open field test(P<0. 05. P<0. 01,P<0. 001). PN significantly reduced the serum levels of inflammation markers( P<0. 05. P<0. 01,P<0. 001), as shown by enzyme-linked immunosorbent assay, and neurotransmitter analysis revealed that PN significantly increased the levels of serotonin and acetylcholine in the mouse hippocampus(P<0. 05). RT-qPCR showed that PN demonstrated the mRNA expression of SLC6A4(P<0. 05. P<0. 01,P<0. 001). Conclusions PN may improve depressive-like behavior in mice by modulating serotonin and acetylcholine levels, inhibiting inflammatory responses, participating in immune regulation, and exerting neuroprotective effects.