Background <p>Delayed encephalopathy due to acute carbon monoxide poisoning (DEACMP) is a severe complication after carbon monoxide (CO) poisoning. However, the sensitivity and specificity of known risk factors for predicting the development of DEACMP remain suboptimal. This study aimed to explore the role of cognitive reserve (CR)-an active mechanism modulating cognitive function in neurological diseases, on the development of DEACMP.</p> Methods <p>Ninety-four patients with first-ever CO poisoning were recruited from Nanchong Central Hospital. Cognitive assessments were conducted at 3 and 12 months post-CO poisoning. Logistic regression and linear mixed-effect regression were used to elucidate the influence of CR on DEACMP occurrence and developmental trajectories of cognition.</p> Results <p>Our results indicated that CR score, C-reactive protein (CRP) level, hyperbaric oxygen (HBO) sessions and glucocorticoid treatment were identified as independent factors associated with DEACMP development. The area under Receiver-operating characteristic (ROC) curve was 0.910 for CR score, with 86.7% sensitivity and 84.4% specificity for predicting DEACMP. Furthermore, our results revealed that higher CR score was associated with slower deterioration in Mental State Examination (MMSE), Activities of Daily Living (ADL) and clinical dementia rating (CDR) scores in post-CO poisoning patients.</p> Conclusions <p>Our study suggests that CR acts as an early predictive factor for DEACMP development, and proactive administration of HBO and glucocorticoid treatments are crucial for preventing DEACMP occurrence. Furthermore, CR predicts a better cognitive trajectory, suggesting that cognitive training may delay cognitive decline in patients after acute CO poisoning.</p>