Objective To investigate the potential active ingredients of Rhodiola rosea-Euonymus alatus medicine (Tianyu medicine) in combating rheumatoid arthritis (RA), and its regulatory effect on the Keap1 / Nrf2 /HO-1 signaling in oxidative stress. Methods UPLC-MS / MS was employed to detect the blood components of Tianyu medicine in blood. A collagen-induced arthritis (CIA) rat model was established, and the effects of Tianyu medicine on RA were evaluated by observing joint swelling, arthritis scores, and thymus and spleen indices. The effects of Tianyu medicine on oxidative stress-related indicators in CIA rats were assessed by measuring serum SOD, CAT,GSH-Px, and MDA levels using enzyme-linked immunosorbent assays. Western blot analysis and quantitative PCR techniques were used to explore the impact of Tianyu medicine on Keap1 / Nrf2 / HO-1 signaling-related protein and mRNA expression in rat synovial tissue. Results The blood components of Tianyu medicine included 43 compounds;these were primarily alkaloids, steroids, and terpenoids, followed by organic acids, hormones, and phenolic compounds. In vivo experiments showed that rats in the model group exhibited increased inflammation and oxidative stress compared with the control group. Rats treated with Tianyu medicine had significantly reduced joint swelling,arthritis scores, and thymus indices compared with the model group (P<0. 05, P<0. 01); additionally, serum SOD,GSH-Px, and CAT levels were significantly increased, while MDA levels decreased (P<0. 05, P<0. 01, P<0. 001).Keap1 expression was downregulated ( P<0. 01, P<0. 001 ), while nuclear Nrf2 and HO-1 expression were upregulated (P<0. 05, P<0. 001). Conclusions Tianyu medicine regulated Keap1 / Nrf2 / HO-1 signaling, inhibited oxidative stress, and alleviated the pathological progression of RA.