BACKGROUND: Total knee arthroplasty (TKA) is considered an effective treatment for pain relief and improved physical performances in end-stage knee osteoarthritis. However, several studies have reported less favorable outcomes after TKA with chronic pain rates of approximately 20%. Exercise might be an effective treatment strategy for chronic pain following TKA, but no randomized controlled trials have evaluated its effect. Therefore, the purpose of this randomized controlled trial is to investigate whether a 12-week neuromuscular exercise (NEuroMuscular EXercise training program for patients with knee or hip osteoarthritis assigned for total joint replacement; NEMEX-TJR) program combined with pain neuroscience education (PNE) provides greater pain relief and improvement in physical performances than PNE alone at 12 months follow-up in a population of patients with chronic pain after primary TKA. METHODS: For this randomized controlled superiority trial, 120 patients with moderate-to-severe chronic pain after TKA are recruited from Aalborg University Hospital, Denmark. Patients are randomly assigned in a 1:1 ratio to one of two interventions: (a) NEMEX-TJR twice weekly for 12 weeks combined with two sessions of PNE or (b) two sessions of PNE given over 6 weeks. Assessment is performed at baseline before intervention and at 3, 6, and 12 months after initiation of the intervention. Outcome assessors are blinded toward group allocation. The primary outcome is the change in the Knee Injury and Osteoarthritis Outcome Score (KOOS), defined as the mean score for the KOOS subscales pain, symptoms, activities of daily living, and quality of life. Secondary outcomes include all KOOS subscale scores and scores for PainDETECT, the Fear-Avoidance Beliefs Questionnaire, Global Perceived Effect, the Pain Catastrophizing Scale, pain intensities, temporal summation, conditioned pain modulation, and pressure pain thresholds. Physical performances are measured with walking, stair climbing, and chair standing tests as well as tests of muscle strength and power. DISCUSSION: The findings will be useful in establishing effective treatment strategies for chronic pain after TKA. The randomized controlled trial involves rigorous scientific methods and uses clinically applicable interventions. The study interventions are conducted in clinical settings, thereby enhancing the possibility of future implementation of the treatments in the health care systems. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03886259. Registered 22 March 2019. Ethics committee registration: N-20180046.