BackgroundKinesiotherapy is an option to mitigate worsening neuropsychomotor function due to human aging. Moreover, exergames are beneficial for the practice of physical therapy by older patients. Physical exercise interventions are known to alter the epigenome, but little is known about their association with exergames.ObjectiveWe aim to evaluate the effects of kinesiotherapy with exergaming on older women’s epigenetic marks and cognitive ability, as well as on their clinical functional variables. Our hypothesis states that this kind of therapy can elicit equal or even better outcomes than conventional therapy.MethodsWe will develop a virtual clinic exergame with 8 types of kinesiotherapy exercises. Afterward, we will conduct a 1:1 randomized clinical trial to compare the practice of kinesiotherapy with exergames (intervention group) against conventional kinesiotherapy (control group). A total of 24 older women will be enrolled for 1-hour sessions performed twice a week, for 6 weeks, totaling 12 sessions. We will assess outcomes using epigenetic blood tests, the Montreal Cognitive Assessment test, the Timed Up and Go test, muscle strength grading in a hydraulic dynamometer, and the Game Experience Questionnaire at various stages.ResultsThe project was funded in October 2019. Game development took place in 2020. Patient recruitment and a clinical trial are planned for 2021.ConclusionsResearch on this topic is likely to significantly expand the understanding of kinesiotherapy and the impact of exergames. To the best of our knowledge, this may be one of the first studies exploring epigenetic outcomes of exergaming interventions.Trial RegistrationBrazilian Clinical Trials Registry/Registro Brasileiro de Ensaios Clínicos (ReBEC) RBR-9tdrmw; https://ensaiosclinicos.gov.br/rg/RBR-9tdrmw.International Registered Report Identifier (IRRID)DERR1-10.2196/32729