BACKGROUND: Our previous studies showed that laser moxibustion may be effective in alleviating the symptoms of knee osteoarthritis. However, the therapeutic effect in patients with different Kellgren-Lawrence (KL) grades is still unclear. We aimed to compare the efficacy of laser moxibustion in the treatment of knee osteoarthritis with different KL grades. METHODS: A total of 392 symptomatic KOA patients with different KL grades were randomly assigned to the laser treatment or sham laser control group (1:1). The patients received laser moxibustion treatment or sham treatment 3 times a week for 4 weeks. Outcomes were measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores and Visual Analog Scale (VAS) scores, and the primary outcome measurement was the change in WOMAC pain scores from baseline to week 4. RESULTS: Among 392 randomized participants, 364 (92.86%) completed the trial. Participants with KL grades 2, 3, and 4 had significantly higher pain, functional, and total WOMAC scores than those with KL grade 1. Spearman correlation test results showed a positive correlation between KL grade and WOMAC pain, function, stiffness scores, and WOMAC total scores. That is, the higher the KL grade, the higher the WOMAC pain, function, stiffness, and WOMAC total scores. After 4 weeks of treatment, patients with KL grades 2 and 3 had significantly higher improvement scores in pain, function, and total scores than those with KL grade 1, whereas those with KL grade 2 had significantly higher improvement scores in stiffness than those with KL grade 1. Patients with KL grade 4 showed no significant effects after laser moxibustion treatment. CONCLUSION: Laser moxibustion is effective for pain reduction and functional improvement in the treatment of KOA with KL grades 2 and 3.