Recent studies show that musculoskeletal conditions contribute significantly to years lived with disability considering the entire global population. Pain and functional disability are the main problems that people with these conditions suffer. Neural mobilization has been shown to be an effective intervention in the treatment of musculoskeletal pain within individual trials, also contributing to improved functionality. Some systematic reviews have been carried out during the last years with the aim of synthesizing the scientific evidence on the use of neural mobilization techniques in the treatment of musculoskeletal disorders. However, they varied a lot in the methodological approaches and, consequently, in the findings and conclusions. Thus, this document is a planned protocol of a comprehensive systematic review with meta-analysis that we intend to carry out to review the scientific literature regarding up-to-date evidence on the use of neural mobilization in the management of people suffering from musculoskeletal pain disorders. The study designs that we will consider as inclusion criteria will be randomized and quasi-randomized clinical trials. The target population will be adults and older adults with musculoskeletal pain. Any controlled trial using any neural mobilization technique as an intervention in one of the trial groups will be included. The main outcomes of interest will be pain, functional status, and physical performance tests (muscle strength, flexibility, and balance). There will be no restrictions on follow-up time or type of setting. The risk of bias of the included studies will be assessed by the RoB 2 tool and the certainty of the evidence will be evaluated using the comprehensive Assessment, Development and Assessment of Assessment Recommendation (GRADE) approach. We intend to present the findings through narrative descriptions and, if possible, through meta-analytic statistics. Trial registration: PROSPERO registration number. CRD42021288387.