OBJECTIVE: To evaluate the evidence for the effectiveness of neuroscience education (NE) for pain, disability, anxiety, and stress in chronic musculoskeletal (MSK) pain. DATA SOURCES: Systematic searches were conducted on Biomed Central, BMJ.com, CINAHL, the Cochrane Library, NLM Central Gateway, OVID, ProQuest (Digital Dissertations), PsycInfo, PubMed/Medline, ScienceDirect, and Web of Science. Secondary searching (PEARLing) was undertaken, whereby reference lists of the selected articles were reviewed for additional references not identified in the primary search. STUDY SELECTION: All experimental studies including randomized controlled trials (RCTs), nonrandomized clinical trials, and case series evaluating the effect of NE on pain, disability, anxiety, and stress for chronic MSK pain were considered for inclusion. Additional limitations: studies published in English, published within the last 10 years, and patients older than 18 years. No limitations were set on specific outcome measures of pain, disability, anxiety, and stress. DATA EXTRACTION: Data were extracted using the participants, interventions, comparison, and outcomes (PICO) approach. DATA SYNTHESIS: Methodological quality was assessed by 2 reviewers using the Critical Review Form-Quantitative Studies. This review includes 8 studies comprising 6 high-quality RCTs, 1 pseudo-RCT, and 1 comparative study involving 401 subjects. Most articles were of good quality, with no studies rated as poor or fair. Heterogeneity across the studies with respect to participants, interventions evaluated, and outcome measures used prevented meta-analyses. Narrative synthesis of results, based on effect size, established compelling evidence that NE may be effective in reducing pain ratings, increasing function, addressing catastrophization, and improving movement in chronic MSK pain. CONCLUSIONS: For chronic MSK pain disorders, there is compelling evidence that an educational strategy addressing neurophysiology and neurobiology of pain can have a positive effect on pain, disability, catastrophization, and physical performance.