The pathophysiology of delirium remains poorly understood. Low leptin level has been associated with features leading to delirium such as dysregulated immune functions and loss of neuroprotective effects. The purpose of the present study was to investigate the relationship between plasma leptin level at intensive care unit (ICU) entry and subsequent occurrence of delirium in critically ill patients. This single-center prospective cohort study in China allocated 336 critically ill patients admitted to ICU between 05/2015 and 05/2016 into a delirium group (n = 102) and non-delirium group (n = 234) based on whether delirium occurred during their stay at the ICU. Patients were examined at least twice daily and delirium was diagnosed using the Confusion Assessment Method for the ICU (CAM-ICU). Blood samples were obtained after ICU entry. Plasma leptin concentrations were measured by ELISA. Delirium occurred in 30.4% (102/336) of patients. Patients who developed delirium showed significantly lower leptin level at ICU entry than those who did not (6.1 ± 3.2 vs. 9.2 ± 5.9 ng/mL; P < 0.001). Low plasma leptin level at ICU entry was independently associated with subsequent occurrence of delirium (OR, 0.865; 95%CI, 0.802–0.934; P < 0.001). Other independent risk factors for delirium included increasing age (OR, 1.050; 95%CI, 1.020–1.080; P = 0.001) and Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score (OR, 1.148; 95%CI, 1.092–1.208; P < 0.001). Patients who developed delirium had a prolonged duration of ICU stay and higher mortality. Low plasma leptin level at ICU entry was associated with the occurrence of delirium in critically ill patients.