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OBJECTIVES:. Administrative databases are increasingly used in research studies to capture clinical outcomes such as sepsis. This systematic review and meta-analysis examines the accuracy of International Classification of Diseases, 10th revision (ICD-10), codes for identifying sepsis in adult and pediatric patients. DATA SOURCES:. We searched MEDLINE, EMBASE, Web of Science, CENTRAL, Epistemonikos, and McMaster Superfilters from inception to September 7, 2021. STUDY SELECTION:. We included studies that validated the accuracy of sepsis ICD-10 codes against any reference standard. DATA EXTRACTION:. Three authors, working in duplicate, independently extracted data. We conducted meta-analysis using a random effects model to pool sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). We evaluated individual study risk of bias using the Quality Assessment of Diagnostic Accuracy Studies tool and assessed certainty in pooled diagnostic effect measures using the Grading of Recommendations Assessment, Development, and Evaluation framework. DATA SYNTHESIS:. Thirteen eligible studies were included in the qualitative synthesis and the meta-analysis. Eleven studies used manual chart review as the reference standard, and four studies used registry databases. Only one study evaluated pediatric patients exclusively. Compared with the reference standard of detailed chart review and/or registry databases, the pooled sensitivity for sepsis ICD-10 codes was 35% (95% CI, 22–48, low certainty), whereas the pooled specificity was 98% (95% CI: 98–99, low certainty). The PPV for ICD-10 codes ranged from 9.8% to 100% (median, 72.0%; interquartile range [IQR], 50.0–84.7%). NPV ranged from 54.7% to 99.1% (median, 95.9%; interquartile range, 85.5–98.3%). CONCLUSIONS:. Sepsis is undercoded in administrative databases. Future research is needed to explore if greater consistency in ICD-10 code definitions and enhanced quality measures for ICD-10 coders can improve the coding accuracy of sepsis in large databases.