OBJECTIVE: We aimed to examine whether targeting spinal manipulative therapy (SMT), by applying the intervention to a specific vertebral level, produces superior clinical outcomes than a nontargeted approach in patients with nonspecific low back pain. DESIGN: Systematic review with meta-analysis. LITERATURE SEARCH: MEDLINE, Embase, CENTRAL, CINAHL, Scopus, PEDro, and Index to Chiropractic Literature were searched up to May 31, 2023. STUDY SELECTION CRITERIA: Randomized controlled trials comparing targeted SMT (mobilization or manipulation) to a nontargeted approach in patients with nonspecific low back pain, and measuring the effects on pain intensity and patient-reported disability. DATA SYNTHESIS: Data extraction, risk of bias, and evaluation of the overall certainty of evidence using the GRADE approach were performed by 2 authors independently. Meta-analyses were performed using the restricted maximum likelihood method. RESULTS: Ten randomized controlled trials (n = 931 patients) were included. There was moderate-certainty evidence of no difference between targeted SMT and a nontargeted approach for pain intensity at postintervention (weighted mean difference = -0.20 [95% CI: -0.51, 0.10]) and at follow-up (weighted mean difference = 0.05 [95% CI: -0.26, 0.36]). For patient-reported disability, there was moderate-certainty evidence of no difference at postintervention (standardized mean difference = -0.04 [95% CI: -0.36, 0.29]) and at follow-up (standardized mean difference = -0.05 [95% CI: -0.24, 0.13]). Adverse events were reported in 4 trials, and were minor and evenly distributed between groups. CONCLUSION: Targeting a specific vertebral level when administering SMT for patients with nonspecific low back pain did not result in improved outcomes on pain intensity and patient-reported disability compared to a nontargeted approach. J Orthop Sports Phys Ther 2023;53(9):1-11. Epub: 28 July 2023. doi:10.2519/jospt.2023.11962.