Objective To predict the target and explore the mechanism of Gancao Fuzi decoction for the treatment of rheumatoid arthritis (RA) by using network pharmacology and molecular docking. Methods The active ingredients and target genes of 4 kinds of traditional Chinese medicines contained in Gancao Fuzi decoction were searched through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Data on RA were downloaded from Gene Expression Omnibus (GEO) database, and differentially expressed genes in synovium between patients with RA and healthy people were screened and intersected with target genes of active ingredients of Gancao Fuzi decoction to obtain potential targets of Gancao Fuzi decoction for the treatment of RA. The Chinese medicine-active ingredient-disease target network was constructed and the network node degree value was analyzed to screen important key activity scores by Cytoscape 3.7.1 software. Key protein targets of Gancao Fuzi decoction in treatment of RA were obtained by protein-protein interaction (PPI) network analysis. Gene Ontology (GO) analysis and Kyoto Gene and Genome Encyclopedia (KEGG) pathway enrichment analysis of the core targets were performed by Metascape database to predict its mechanism of action. Finally, AutoDockTools-1.5.6 and PyMOL software were used for molecular docking to verify its binding ability. Results Forty-four potential target genes for Gancao Fuzi decoction in treating RA were obtained. The traditional Chinese medicine-active ingredient-disease target network contained 4 nodes of traditional Chinese medicines, 95 nodes of active ingredients and 44 nodes of potential target genes. Network topology analysis showed that the degree of quercetin was the highest and might be the possible key active ingredients of Gancao Fuzi decoction in the treatment of RA. The mechanism of Gancao Fuzi decoction in treating RA involves biological process including response to inorganic sunstance, cellular component including membrane raft, and molecular function including CXCR chemokine receptor binding. KEGG analysis showed that the active ingredients of Gancao Fuzi decoction mainly acted on RA through interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, osteoclast differentiation, and other signaling pathways. PPI network analysis showed that matrix metalloproteinase 9 (MMP9), C-X-C motif chemotactic ligand 8 (CXCL8), peroxisome proliferator activated receptor γ (PPARγ) and epidermal growth factor receptor (EGFR) were the key target molecules of Gancao Fuzi decoction in the treatment of RA. And it was confirmed by molecular docking that quereetin had high affinity with key target molecules MMP9, CXCL8, PPARγ and EGFR. Conclusion The active ingredients in Gancao Fuzi decoction can regulate multiple signaling pathways through MMP9, CXCL8, PPARγ and EGFR to treat RA.