Objective To analyze the effect of eperisone hydrochloride combined with glucosamine hydrochloride on knee osteoarthritis. Methods A total of 99 patients with knee osteoarthritis admitted to Nanyang Nanshi Hospital from June 2020 to June 2022 were selected as the research objects and divided into control group (n=49) and study group (n=50). Patients in the control group were treated with glucosamine hydrochloride, while patients in the study group were treated with glucosamine hydrochloride and eperisone hydrochloride combined treatment. The indexes of oxidative stress and inflammatory factors were detected by ELISA, the knee joint function was evaluated by WOMAC score, and the joint ROM was used to evaluate the degree of joint mobility, and the total effective rate was observed. Results Compared with before treatment, the scores of nitric oxide (NO), malondialdehyde (MDA), TNF-α, MMP-3, interleukin-6 (IL-6), difficulty in daily activities, stiffness and pain in the two groups were decreased after treatment, and those in the study group were lower than the control group (P<0.05). Compared with before treatment, the levels of superoxide dismutase (SOD), active knee flexure ROM, and Lysholm score of the two groups were increased after treatment, and the study group was higher than the control group (P<0.05). Compared with the control group, the total effective rate of the study group was higher (P<0.05). Conclusion The combined treatment of eperisone hydrochloride and glucosamine hydrochloride can reduce TNF-α and MMP-3 in patients with knee osteoarthritis, improve the oxidative stress state of patients, and the clinical effect is good.