Purpose <p>Delirium is frequent and associated with increased health expenditures, unfavourable outcomes and increased mortality. Diagnosis currently relies on clinical scales and is often missed. However, blood-based biomarkers may represent a feasible tool to enhance risk stratification, early diagnosis, and monitoring. We aimed to identify blood-based biomarkers associated with delirium in adult intensive care unit patients, to provide a structured summary of the evidence, and to highlight gaps of knowledge to inform future research.</p> Methods <p>A systematic literature search was performed in PubMed, EMBASE, The Cochrane Library<i>,</i> and Web of Science from inception to 3rd September 2025 with no date or language restrictions. Eligible studies were observational, assessing associations between blood-based biomarkers and delirium in critically ill adults admitted to an intensive care unit. The Newcastle–Ottawa Scale was applied to assess study quality. Data were qualitatively synthesized in a systematic narrative synthesis.</p> Results <p>Out of 2130 records including duplicates, 61 studies were included, comprising 39,355 adult patients, of whom 16,762 were screened positive for delirium. Delirium definition, assessment tools and frequency, reported delirium outcomes, and timing of biomarker sampling varied. In total, 153 blood-based biomarkers were identified, 101 were significantly associated with delirium and 40 were associated with delirium across two studies or more. Study quality was generally poor and substantial study heterogeneity limited comparability.</p> Conclusion <p>Current evidence does not support clinical use of any biomarker. Poor study quality, small sample sizes, and considerable methodological heterogeneity limit interpretation, generalizability, validation, and firm conclusions. Standardized methodology and international consensus are essential in future research.</p>