Abstract: This study aims to explore the molecular mechanism of cellular autophagy in rheumatoid arthritis（RA） regulated by the Sidaxue（SX）. Firstly, a collagen-induced arthritis（CIA） rat model was constructed, and after 21 days of SX administration, the thymus and spleen indices of rats were calculated, the histopathological changes of rat knee synovial joint were observed, and the serum interleukin-6（IL-6） and interleukin-37（IL-37） levels of rats were measured. Further, the possible molecular mechanism of SX regulating cellular autophagy in RA was analyzed using network pharmacology and validated by molecular docking with the help of Autodock vina software, while the pharmacological properties of the main active components of SX were predicted by online database, combined with molecular docking score for primary screening of effector components. Finally, RT-qPCR and Western blot were used to detect the effects of SX on phosphatidylinositol 3-kinase（PI3K）, protein kinase B（AKT）, mammalian target of rapamycin（mTOR） and microtubule-associated protein 1 light chain 3（LC3） mRNA and protein expression in the synovial tissue of CIA rats. The results of animal experiments showed that SX could effectively relieve joint swelling, alleviate the overreaction of immune organs, improve synovial histopathological changes and reduce the levels of inflammatory factors IL-6 and IL-37 in CIA rats（P＜0.05）. Network pharmacology results showed that AKT1, CASP3, BCL2L1 and other targets were more critical, and animal autophagy, apoptosis and PI3K/AKT signaling pathways were associated with RA and had high significance. Molecular docking results showed that key targets of PI3K/AKT signaling pathway stably bound to the main active components of SX, β-sitosterol, Cajinin, ursolic acid, and eleutheroside A may be the superior effector components of SX in regulating autophagy. RT-qPCR and Western blot experimental results showed that SX dose-dependently downregulated PI3K, AKT, mTOR mRNA（P＜0.05） and protein（P＜0.001） expression of PI3K AKT and mTOR, upregulated the expression level of autophagy marker LC3 mRNA（P＜0.05） and promoted the conversion of LC3-Ⅰ to LC3-Ⅱ（P＜0.01）. In conclusion, SX has an ameliorative effect on RA, and its mechanism may be the inhibition of PI3K/AKT/mTOR signaling pathway, which promotes autophagic cell death of synovial cells to inhibit abnormal proliferation of synovial membrane.