Objectives: Oxidative stress after cardiac surgery may disrupt the blood–brain barrier and contribute to postoperative delirium (POD). Although associations between oxidative stress and POD are recognized, whether vitamin C (VC) can prevent POD remains poorly understood. This study aimed to explore the association of VC administration with POD after cardiac surgery. 

Methods: Eighty-four patients undergoing elective cardiac surgery at our hospital were enrolled. The non-VC group (NVC, n = 40) consisted of patients treated between October 2021 and March 2022, while the VC group (n = 44) included those treated between April and September 2022 who received 2 g intravenous VC at intensive care unit (ICU) admission. The primary outcome was POD incidence. Electron spin resonance (ESR) measured AFR/DMSO, which reflected VC before induction, after CPB withdrawal, at ICU admission, and on postoperative day 1. 

Results: Baseline characteristics, comorbidities, and intraoperative factors were similar between groups. Postoperative organ dysfunction and inflammation were also comparable, although lactate levels were 40% higher in the VC group. POD incidence was significantly lower with VC (35.0% vs. 11.4%, p < 0.01). Logistic regression analysis confirmed that VC reduced POD risk (adjusted odds ratio 0.22, 95% CI 0.07–0.69, p < 0.01). ESR showed that postoperative AFR/DMSO levels dropped sharply but normalized by day 1 in VC-treated patients. Conclusions: This study suggests that 2 g of VC administered at ICU admission may reduce POD incidence. In the future, these findings require confirmation in randomized trials.