INTRODUCTION: This study aims to investigate whether a pain neuroscience education (PNE) combined with a blended exercises programme including aerobic, resistance, neuromuscular, breathing, stretching and balance exercises and diet education provides greater pain relief and improvement in functional and psychological factors than PNE and blended exercises alone and whether 'exercise booster sessions (EBS)' approach may improve outcomes and increase adherence in patients with knee osteoarthritis (KOA) (by telerehabilitation (TR)). METHODS AND ANALYSIS: In this single-blind randomised controlled trial, 129 patients (both genders; age >40) diagnosed with KOA will be randomly assigned to one of the 2 treatment combinations as: (1) blended exercises alone (36 sessions over 12 weeks), (2) PNE alone (three sessions over 2 weeks), (3) combination of PNE with blended exercises (exercise three times a week for 12 weeks combined with three sessions of PNE) and (4) a control group. Outcome assessors will be blinded towards group allocation. The primary outcome variables are the visual analogue scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis index in knee osteoarthritis (WOMAC) score. Secondary outcomes include Pain Self-Efficacy Questionnaire (PSEQ), Depression, Anxiety and Stress Scale (DASS), Tampa Scale for Kinesiophobia (TSK), Short Falls Efficacy Scale International (FES-I), Pain Catastrophising Scale (PCS), Short Form Health Survey (SF-12) and Exercise Adherence Rating Scale (EARS), 30 s sit-to-stand test (30CST), Timed Up and Go (TUG), lower limbs' muscle strength and lower limb joints' active range of motion (AROM) will be performed at baseline, 3 and 6 months' postinterventions. The primary and secondary outcomes will assess at baseline, 3 months and 6 months postinterventions.The findings will be useful in establishing an effective treatment strategy covering multiple aspects behind KOA. The study protocol is conducted in clinical settings, thereby enhancing the possibility of future implementation of the treatments in the healthcare systems and self-care management. Results in comparison between groups will help to clarify the most effective of mixed-method TR (blended exercise, PNE, EBS with diet education) on more improvement in pain, functional and psychological factors in patients with KOA. This study will combine some of the most critical interventions, to be able to introduce a 'gold standard therapy' in the treatment of KOA. ETHICS AND DISSEMINATION: The trial has been approved by the ethics committee for research involving human subjects of the Sport Sciences Research Institute of Iran (IR.SSRC.REC.1401.021). The study findings will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: IRCTID: IRCT20220510054814N1.