OBJECTIVE To investigate the mechanism by which Danggui Buxue Decoction (DBD) regulates oxidative stress in rats with rheumatoid arthritis based on phosphatidylinositol 3-kinase (PI3K)/protein kinase B(Akt)/nuclear factor E2-related factor 2(Nrf2) signaling pathway. METHODS Forty-eight Wistar rats were randomly divided into 6 groups [normal group, model group, tripterygium glycosides tablets group(9.45 mg·kg^-1), DBD low dose (3.75 g·kg^-1), medium dose(7.5 g·kg^-1) and high dose group(15 g·kg^-1)]. In addition to the normal group, the other groups were constructed collagen-induced arthritis (CIA) rat model, and given the corresponding drug treatment for 28 days. During the period, the body weight of the rats, the degree of ankle swelling, and the arthritis score were recorded regularly. The levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA) in serum of rats were determined by ELISA. The spleen index and thymus index were calculated. HE staining and safranin O-fast green staining were used to observe the pathological morphology of synovial membrane of knee joint in rats. The expression of PI3K, AKT, Nrf2 and HO-1 mRNA in synovial tissue was determined by qPCR. The expression of p-PI3K/PI3K, p-Akt/Akt, Nrf2 and HO-1 protein in synovial tissue was determined by Western blot. RESULTS Compared with the normal group, the body weight of the rats in the model group was lower (P<0.05), and the bilateral hind limbs were obviously red and swollen or even deformed. Compared with the model group, the body weight of rats in each administration group increased gently (P<0.05), the swelling degree of bilateral hind limbs was significantly reduced (P<0.05), and the arthritis score was significantly decreased (P<0.05). The level of MDA in joint tissue decreased (P<0.05), and the levels of GSH-Px, CAT and SOD increased (P<0.05). The expression of PI3K, Akt, Nrf2 and HO-1 mRNA in PI3K/Akt/Nrf2 pathway was increased (P<0.05). The ratio of p-PI3K/PI3K, p-Akt/Akt and the expression of Nrf2 and HO-1 protein were significantly increased (P<0.05). CONCLUSION DBD may inhibit the level of oxidative stress, attenuate the oxidative damage of synovial tissues and improve the pathological changes of synovium by regulating the PI3K/Akt/Nrf2 pathway in CIA rats, thus exerting an anti-RA effect.