To assess real-world effectiveness of hyperbaric oxygen therapy (HBOT) on delayed neuropsychiatric sequelae (DNS) after carbon monoxide (CO) poisoning we conducted a retrospective review of patients with CO poisoning admitted to Linkou Chang-Gung Memorial Hospital, Taiwan’s largest medical center, during 2009–2015. We included patients developing DNS after CO poisoning and compared improvements in neuropsychiatric function, with and without HBOT, after 12 months post-DNS to understand differences in recovery rates. DNS improvement-associated factors were also evaluated. We used receiver operating characteristic (ROC) curve analysis to assess the role of time elapsed between DNS diagnosis and HBOT initiation in predicting DNS improvement. A total of 62 patients developed DNS, of whom 11 recovered while the rest did not. Possible factors predicting DNS improvement included receiving HBOT post-DNS (72.7% vs 25.5%; P = 0.006), and treatment with more than three HBOT sessions during acute stage CO poisoning (81.8% vs 27.5%; P = 0.003). The relevant area under the ROC curve was 0.789 (95% CI 0.603–0.974), and the best cut-off point was 3 days post-DNS diagnosis, with 87.5% sensitivity and 61.5% specificity. Early HBOT in patients who developed DNS after CO poisoning significantly improved their DNS symptoms, with treatment effects sustained for 1 year after DNS diagnosis.