OBJECTIVE: This systematic review aims to make a mixed comparison of interventions for kinesiophobia and individuals with musculoskeletal pain. METHODS: A comprehensive search strategy was conducted in the database of PubMed, MEDLINE, and Web of Science with the inclusion criteria: (1) randomized controlled design; (2) patients with musculoskeletal pain as participants; (3) treatments protocols of kinesiophobia as interventions or comparisons; (4) the score of Tampa Scale Kinesiophobia (TSK) as outcome measures. A network meta-analysis was used to synthesize the data after checking the model consistency. The risk of bias was assessed by the Cochrane Collaboration Risk of Bias Assessment Tool. RESULTS: Thirty-one studies were included in this review after a comprehensive search strategy with a low risk of bias and good consistency. According to the results of the network meta-analysis, a multi-modal treatment protocol had the highest probability to become the best choice in dealing with kinesiophobia caused by musculoskeletal pain, whereas psychological treatment protocols also showed a potentially positive effect on musculoskeletal pain-induced kinesiophobia. CONCLUSION: Multi-modal protocols could be recommended as the preferred option when dealing with kinesiophobia caused by musculoskeletal pain. However, it is still worth mentioning that there are also potentially positive therapeutic effects of psychological interventions. Since the concept of kinesiophobia is based on the fear-avoidance model, the psychological mechanism should be paid enough attention to during treatment. REGISTRATION NUMBER: CRD42021286450.