BACKGROUND: Delirium is a common neuropsychiatric disorder associated with prolonged hospital stays, and increased morbidity and mortality. Diagnosis is frequently missed due to varying disease presentation and lack of standardized testing. We examined biomarkers as diagnostic or prognostic indicators of delirium, and provide a rational basis for future studies. METHOD: Systematic review of literature published between Jan 2000 and June 2019. Searches included: PubMed; Web of Science; CINAHL; EMBASE; COCHRANE and Medline. Additional studies were identified by searching bibliographies of eligible articles. RESULTS: 2082 relevant papers were identified from all sources. Seventy-three met the inclusion criteria, all of which were observational. These assessed a range of fourteen biomarkers. All papers included were in the English language. Assessment methods varied between studies, including: DSM criteria; Confusion Assessment Method (CAM) or CAM-Intensive Care Unit (ICU). Delirium severity was measured using the Delirium Rating Scale (DRS). Delirium was secondary to post-operative dysfunction or acute medical conditions. CONCLUSION: Evidence does not currently support the use of any one biomarker. However, certain markers were associated with promising results and may warrant evaluation in future studies. Heterogeneity across study methods may have contributed to inconclusive results, and more clarity may arise from standardization of methods of clinical assessment. Adjusting for comorbidities may improve understanding of the pathophysiology of delirium, in particular the role of confounders such as inflammation, cognitive disorders and surgical trauma. Future research may also benefit from inclusion of other diagnostic modalities such as EEG as well as analysis of genetic or epigenetic factors.