BACKGROUND: Knee osteoarthritis (KOA) is associated with decreased quadriceps strength and decreased activation of central motor cortex. It is necessary to investigate intervention strategies that combine central and peripheral treatments. OBJECTIVE: To assess the effectiveness of high-frequency repetitive transcranial magnetic stimulation (rTMS) in conjunction with quadriceps strength training for 12 weeks in the treatment of KOA. DESIGN: Prospective, randomized, single-blind, comparative effectiveness study. METHODS: In this 12-week randomized controlled clinical trial, 48 eligible patients were randomly allocated to either an experimental group or a control group. The experimental group underwent high-frequency rTMS in conjunction with quadriceps strength training, whereas the control group received sham rTMS alongside quadriceps strength training. The primary outcome measure was the visual analog scale (VAS), while secondary outcome measures included the University of Western Ontario and McMaster University Osteoarthritis Index (WOMAC), the peak torque of the extensor muscles, the peak torque of the flexor muscles, and the flexion-extension ratio. A two-way repeated measures analysis of variance with group as a group factor and time factor was used to calculate the effects of the interventions on all outcome measures. RESULTS: Forty-four of the 48 patients who were allocated at random finished the study. Twelve weeks later, the VAS index in the experimental group decreased from 3.14 ± 1.13 to 1.36 ± 0.85, and that in the control group decreased from 3.23 ± 1.15 to 2.18 ± 1.40 ( < 0.05). At the same time, the WOMAC score, the peak torque of the extensor muscles, the peak torque of the flexor muscles, and the flexion-extension ratio were improved in the two groups ( < 0.05), and the experimental group was significantly better than the control group ( < 0.05). CONCLUSION: High-frequency rTMS combined with quadriceps strength training for 12 weeks can effectively improve pain, muscle strength and joint function in patients with KOA. TRIAL REGISTRATION: Chinese Clinical Trial Registry (https://www.chictr.org.cn/) ChiCTR2300067617.