BackgroundThe increasing prevalence of knee osteoarthritis and total knee arthroplasty (TKA) impose a significant socioeconomic burden in developed and developing countries. Prehabilitation (rehabilitation in the weeks immediately before surgery) may be crucial to prepare patients for surgery improving outcomes and reducing assistance costs. Moreover, considering the progress of telemedicine, candidates for TKA could potentially benefit from a tele-prehabilitation programme. We aim to evaluate the effects of a home-based tele-prehabilitation program for patients waiting for total knee replacement.Methods and analysisForty-eight male patients, aged 65–80, on a waiting list for TKA will be recruited and randomly assigned to the tele-prehabilitation intervention or control groups. Both groups will undergo the same 6-week exercise program (five sessions/week) and the same educational session (one per week). The tele-prehabilitation group will perform asynchronous sessions using a tablet, two accelerometers and a balance board (Khymeia, Padova, Italy), while the control group will use a booklet. The Western Ontario and McMaster Universities Osteoarthritis Index Questionnaire, at the end of the prehabilitation, will be the primary outcome. Secondary outcomes will include self-reported outcomes, performance tests and change in expressions of blood and muscle biomarkers. Ten healthy subjects, aged 18–30, will be also recruited for muscle and blood samples collection. They will not undergo any intervention and their data will be used as benchmarks for the intervention and control groups’ analyses.Ethics and disseminationThis randomised controlled trial will be conducted in accordance with the ethical principles of the Declaration of Helsinki. This study has been approved by the Ethics Committee of Vita-Salute San Raffaele University (Milan, Italy. No. 50/INT/2022). The research results will be published in peer-reviewed publications.Trial registration numberNCT05668312.