ObjectiveTo compare the effect of Neuromuscular Exercise (NME) plus Pain Science Education (PSE), Isolated NME, and usual care on brain function measured by electroencephalography (EEG), clinical, and psychosocial outcomes in patients with chronic pain due to knee osteoarthritis (KOA).MethodsA three-arm randomised controlled trial will be conducted. Fifty-seven participants with KOA will be recruited in a 1:1:1 ratio. Outcome assessor, and statistician will be blinded to group allocation. One experimental group (n = 19) will receive NME plus PSE (24 sessions, 60-90 min each), the other experimental group (n = 19) will receive isolated NME (24 sessions, 60-90 min each) and the control group (n = 19) will continue with usual care. The PSE will be adapted to the context of the participants. Primary outcome measures will be brain activity, and secondary outcomes will be pressure pain threshold, pain intensity, disability, fear-avoidance beliefs, self-efficacy, and pain catastrophizing. Outcome measures will be evaluated pre-intervention, immediately post-intervention, and four-month post-intervention.ConclusionThe NME plus PSE intervention approach proposed in this trial could expand multimodal intervention strategies for patients with KOA.ImpactNME plus PSE applied by a physical therapist could be essential in improving brain function, clinical, and psychosocial outcomes of patients with KOA. This could have a positive impact on the use of these therapeutic modalities from a multidimensional approach, and this combined protocol could potentially be a guide for health professionals.