BACKGROUND: Musculoskeletal injuries and conditions affect millions of individuals. These ailments are typically managed by immobilization, physiotherapy, or activity modification. Regenerative medicine has experienced tremendous growth in the past decades, especially in musculoskeletal medicine. Umbilical cord-derived Wharton's jelly is an exciting new option for such therapies. Wharton's jelly is a connective tissue located within the umbilical cord largely composed of mesenchymal stem cells and extracellular matrix components, including collagen, chondroitin sulfate, hyaluronic acid, and sulfated proteoglycans. Wharton's jelly is a promising and applicable biologic source for orthopedic regenerative application. METHODS: A systematic search will be conducted in PubMed, ScienceDirect, and Google Scholar databases of English, Italian, French, Spanish, and Portuguese language articles published to date. References will be screened and assessed for eligibility by two independent reviewers as per PRISMA guidelines. Articles will be considered without exclusion to sex, activity, or age. Studies will be included if they used culture-expanded, mesenchymal stem/stromal cells of mesenchymal stem cells and/or connective tissue obtained from Wharton's jelly. Studies will be excluded if Wharton's jelly is not the sole experimental examined cell type. Placebos, conventional non-operative therapies including steroid injections, exercise, and NSAIDs will be compared. The study selection process will be performed independently by two reviewers using a reference software. Data synthesis and meta-analysis will be performed separately for clinical and pre-clinical studies. DISCUSSION: The results will be published in relevant peer-reviewed scientific journals. Investigators will present results at national or international conferences. TRIAL REGISTRATION: The protocol was registered on PROSPERO international prospective register of systematic reviews prior to commencement, CRD42020182487 .