Background: Delirium is common in old patients who undergo cardiac surgery, and it is associated with adverse outcomes. The genesis of delirium is thought to be multi-factorial, but it is still not well understood. Symptoms of depression and elevated cortisol level have been described in some previous studies as factors associated with delirium, suggesting a shared pathophysiology. Aims: The objective of the present study was to determine whether preoperative depression symptoms and increased cortisol level represent risk factors for delirium after cardiac surgery. Methods: We performed a prospective cohort study in 183 patients aged >50 years undergoing elective cardiac surgery. The Geriatric Depression Scale (GDS) was used to assess patients for depressive symptoms before surgery. Preoperative plasma cortisol levels were available in 145 participants. Delirium was diagnosed using the Confusion Assessment Method for Intensive Care Unit (CAM-ICU) during the first 7 days after surgery. Spearman correlation was used for correlations between GDS, Mini-Mental State Examination (MMSE), Charlson comorbidity index, and age. Binary logistic regression was used to determine whether GDS and cortisol levels predict postoperative delirium. Results: Delirium occurred in 60 patients out of 183 (32.8%) included and lasted 2.3 days (SD 1.36). GDS was correlated with age (p = 0.001) and comorbidity index (p = 0.003) and inversely correlated with MMSE score (p < 0.001). Higher preoperative GDS scores were associated with incidence of delirium in the postoperative period (p = 0.002). The association was significant after controlling for age, MMSE score, history of stroke, and Charlson comorbidity index (p = 0.045). Preoperative cortisol level was not associated with the development of postoperative delirium. Conclusion: Our results suggest that a higher preoperative depression score is associated with an increased risk of postoperative delirium. On the other hand, preoperative plasma cortisol level does not seem to be a predictor of delirium after surgery. Further studies are needed to determine the potential of preoperative depression treatment to prevent postoperative delirium.