Qufeng Zhitong capsule (QFZTC) is a traditional Chinese herbal formula with potential therapeutic efficacy in rheumatoid arthritis (RA). This study seeks to clarify the potential effects and mechanisms of QFZTC against RA. Active compounds and targets of QFZTC were retrieved from the Herbal Ingredients' Targets (HIT), Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and Traditional Chinese Medicine Integrated Database (TCMID) databases. RA-related targets were searched on GeneCards and DisGeNET databases. Protein-protein interaction (PPI) network was established using the STRING database. Gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) enrichment analyses were performed on hub targets. Molecular docking was conducted on hub targets and active compounds. High-performance liquid chromatography (HPLC) was applied to characterize the active compounds in QFZTC. RA-fibroblast like synoviocytes (RA-FLSs) were cultured and treated by QFZTC-containing serum, in which proinflammatory cytokines and hub targets were detected. Cell viability was determined by cell counting kit-8 (CCK-8) assay. A total of 360 active compounds and 445 potential targets are identified for QFZTC against RA. Protein-protein interaction (PPI) network determined five hub targets, interleukin 6 (IL6), IL1B, VEGFA, JUN, and tumor necrosis factor (TNF). GO and KEGG analyses revealed that the MAPK pathway may be a critical signaling in QFZTC treating RA. Molecular docking showed that luteolin, kaempferol, and myricetin has good affinity with TNF, and they were identified by HPLC. <i>In vitro</i> experiments confirmed that QFZTC restrained the cell viability and inflammation in RA. This study revealed the active compounds and molecular targets for QFZTC treating RA. QFZTC is a promising drug and ameliorates RA by inhibiting inflammatory response.