OBJECTIVE: The cause of increased knee pain related to quadriceps weakness in knee osteoarthritis remains unclear. This study aimed to assess the impact of alterations in the effusion-synovitis, a special kind of nociceptive structure, on changes in knee pain associated with quadriceps weakness. METHODS: Based on the osteoarthritis initiative cohort, knees with comprehensive records of quadriceps strength, effusion-synovitis, and knee pain assessments at baseline, 12-month and 24-month intervals were included. Quadriceps strength was measured isometrically at baseline, while effusion-synovitis and knee pain were assessed at baseline, 12-month, and 24-month follow-ups. Effusion-synovitis was assessed using the Magnetic Resonance Imaging Osteoarthritis Knee Score while knee pain was evaluated with the Western Ontario and McMaster Universities Osteoarthritis Index. Mediation-effect models were utilized to quantify the extent to which changes in effusion-synovitis, induced by quadriceps weakness, could mediate the impact on the knee pain scale. RESULTS: The analysis involved 1377 knees of 1235 participants with both baseline and 12-month follow-up data (61.1% females, mean age of 61.7 years). Baseline quadriceps strength was significantly associated with knee pain changes over 12 and 24 months, while changes in effusion-synovitis were also directly associated with worsening knee pain at 12- and 24-month follow-ups. More importantly, effusion-synovitis changes mediated the association between baseline quadriceps strength and knee pain worsening over 12 and 24 months, with the mediating proportion of 17.72% and 10.31%, respectively. Additionally, this mediation association remained significant in the population with radiographic osteoarthritis during 12-month follow-up. CONCLUSION: Effusion-synovitis mediates approximately one-fifth of the association between baseline quadriceps strength and knee pain changes, suggesting that interventions targeting effusion-synovitis could facilitate the treatment of knee pain, especially caused by quadriceps weakness.