<p>Heparin-Binding Protein (HBP) is a granule protein derived from neutrophils, located in secretory vesicles and neutrophilic granules, also known as cationic antimicrobial protein of 37&#xa0;kDa (CAP37) or azurocidin. This study evaluates the diagnostic and prognostic value of HBP levels in relation to infection, organ dysfunction, and mortality in adult patients. A systematic review and meta-analysis were conducted by searching PubMed, Web of Science, EMBASE, and the Cochrane Database from their inception through June 2023. Original studies assessing HBP levels' diagnostic and prognostic utility in predicting infection and disease severity in critically ill adult patients were included. The primary outcome was the diagnostic and predictive role of HBP in infection and severity. The Quality Assessment of Diagnostic Accuracy Studies 2 tool was used to evaluate bias risk. The study is registered with PROSPERO (CRD42023421081). A total of 56 studies involving 11,486 patients were included. Pooled analysis showed HBP had a sensitivity of 0.87 (95% CI, 0.82–0.91), specificity of 0.87 (95% CI, 0.79–0.92), and an AUC of 0.93 (95% CI, 0.91–0.95) for infection diagnosis. For prognostic assessment, sensitivity was 0.77 (95% CI, 0.74–0.80), specificity was 0.72 (95% CI, 0.68–0.76), and AUC was 0.81 (95% CI, 0.78–0.85). HBP outperformed procalcitonin (PCT), C-reactive protein (CRP), and white blood cell count (WBC) in diagnosing and predicting critical illness. No publication bias was detected. HBP demonstrates high sensitivity and specificity for diagnosing infections in critically ill adult patients. Additionally, it effectively predicts disease progression, including organ dysfunction and mortality, surpassing traditional biomarkers such as PCT, CRP, and WBC.</p>