Abstract Objective This study examined the association between pre-operative olfactory performance and delirium after cardiac surgery. As a secondary aim, we examined the relationship between baseline olfaction, cognitive functioning, and plasma neurofilament light (NfL). Method Individuals undergoing cardiac surgery were recruited as part of a clinical trial in which blood pressure during bypass was targeted using cerebral autoregulation monitoring. There were 189 participants (mean age = 70 years; 75% men). At baseline, olfaction, cognition, and plasma concentrations of NfL were assessed using the 12-item Brief Smell Identification Test (BSIT), a battery of neuropsychological tests, and the Simoa™ NF-Light Assay, respectively. Impaired olfaction was defined as a score of ≤8 for men and ≤ 9 for women. Delirium was assessed using the Confusion Assessment Method (CAM) and CAM-ICU, and delirium severity was assessed using the Delirium Rating Scale-Revised-1998 (DRS-R-98). The association of baseline olfaction and delirium and delirium severity was examined in regression models adjusting for age, duration of bypass, a surgery risk score, and baseline cognitive performance. Results In adjusted models, impaired olfaction at baseline was associated with both incident delirium (OR = 2.25, p = 0.04) and greater delirium severity (OR = 2.10, p = 0.04) after cardiac surgery. Furthermore, worse baseline olfaction was associated with impaired cognition (p < 0.001) and increased perioperative concentrations of plasma NfL (p = 0.04). Conclusions Pre-operative olfactory testing may provide insight into brain vulnerability, cognitive dysfunction, and delirium risk in individuals undergoing cardiac surgery. Psychophysical olfactory assessment may inform strategies for patient risk stratification and early identification of individuals at risk for post-operative delirium, allowing for delirium-prevention strategies.