We aimed to evaluate whether cognitive functional therapy (CFT) is an effective treatment for adults with chronic low back pain (LBP). Intervention systematic review with meta-analysis. We searched 4 electronic databases (CENTRAL, CINAHL, MEDLINE, and Embase) and 2 clinical trial registers (ClinicalTrials. gov and the EU Clinical Trials Register) from inception up to March 2022. We included randomized controlled trials evaluating CFT for adults with LBP. The primary outcomes were pain intensity and disability. Secondary outcomes were psychological status, patient satisfaction, global improvement, and adverse events. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. Random-effects meta-analysis with the Hartung-Knapp-Sidik-Jonkman adjustment was used to estimate pooled effects. Fifteen trials were included (9 ongoing and 1 terminated), of which 5 provided data (n = 507; n = 262 CFT, and n = 245 control). There was very low certainty for the effectiveness of CFT compared to manual therapy plus core exercises (2 studies, n = 265) for reducing pain intensity (mean difference: -1.02/10, 95% confidence interval: -14.75, 12.70) and disability (mean difference: -6.95/100, 95% confidence interval: -58.58, 44.68). Narrative synthesis showed mixed results for pain intensity, disability, and secondary outcomes. No adverse events were reported. All studies were judged to be at high risk of bias. Cognitive functional therapy may not be more effective than other common interventions for reducing pain and disability in adults with chronic LBP. The effectiveness of CFT is very uncertain and will remain so until higher-quality studies are available. .