Objectives:This study evaluated the efficacy of hyperbaric oxygen therapy (HBOT) combined with butylphthalide (NBP) and oxiracetam (OXR) for vascular cognitive impairment after acute ischemic stroke and investigated the association between such combination therapy and the serum levels of inflammatory markers.Methods:This was a prospective study which included eighty patients with post-AIS cognitive impairment (PAISCI) treated in Dongguan City People’s Hospital from January 2020 to January 2022. They were randomized into study group and control group. The control group was provided with conventional therapy consisting of NBP for intravenous transfusion and oral OXR, while the study group received combination therapy of HBOT, NBP, and OXR. A comparison was drawn between the two groups regarding clinical outcomes, levels of recovery of cognitive and neurological function and intelligence, changes in inflammatory markers, and incidence of adverse drug reactions (ADRs).Results:The response rate of the study group was significantly higher than that of the control group (p=0.04). The cognitive function scores of the study group were significantly better than those of the control group at the end of treatment (p<0.05). The post-treatment levels of inflammatory markers were significantly reduced in the study group when compared with the control group (p<0.05). At two weeks after treatment, the ADR rate of study group was significantly lower than the control group (p=0.03).Conclusions:The combination therapy of HBOT, NBP, and OXR demonstrates robust efficacy in patients with PAISCI. It is deemed to be a safe and effective treatment regimen.