Objective To explore the effect and action of remazolam on brain injury caused by sepsis. Methods Male C57BL/6J mice were randomly separated into sham operation, model, remazolam (8 mg/ kg), remazolam + Sirt1 inhibitor (EX527) (8 mg/ kg remazolam + 5 mg/ kg EX527), and EX527 groups by the random number table method, with 38 rats in each group. A sepsis-associated encephalopathy (SAE) mouse model was established by cecal ligation and puncture. After the corresponding intervention was given, the survival rates of mice within seven days after the operation were observed and recorded, and a Morris water maze was used to detect the mice’s escape latency and number of times crossing the platform. Twenty-four hours after surgery, blood-brain barrier (BBB) permeability was assessed by Evans blue (EB) leakage; the levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β in brain tissue were detected by enzyme-linked immunosorbent assay; the levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD) and catalase (CAT) in brain tissue were detected by chemical colorimetry. Histopathological changes to the hippocampus were observed by HE staining, and neuronal apoptosis was detected using the TUNEL method. Western Blot was used to detect the expression of silent information regulator 1 (Sirt1) / forkhead box O1 (FoxO1) pathway-related proteins in the hippocampus. Results Compared with the sham group, mice in the model group had a significantly decreased survival rate, platform crossing time, SOD and CAT activities, and Sirt1 and cytoplasmic NF-κB p65 protein levels and significantly increased brain tissue EB content; IL-6, TNF-α, IL-1β, and MDA levels; hippocampal neuron apoptosis index; acetylated FoxO1 (Ac-FoxO1) / FoxO1 ratio; and acetylated nuclear factor-κB p65 (Ac-NF-κB p65) and nuclear NF-κB p65 protein levels (all P< 0. 05). Compared with the model group, mice in the remazolam group had a significantly increased survival rate, platform crossing time, SOD and CAT activities, and Sirt1 and cytoplasmic NF-κB p65 protein levels, and significantly decreased escape latency; brain tissue EB content; IL-6, TNF-α, IL-1β, and MDA levels; hippocampal neuron apoptosis index; Ac-FoxO1/ FoxO1 ratio; and Ac-NF-κB p65 and nuclear NF-κB p65 protein levels (all P< 0. 05). EX527 inhibited the expression of Sirt1 and substantially attenuated the above protective effects of remazolam in SAE mice (all P< 0. 05). Conclusions Remazolam improved the survival rate of mice with sepsis and reduced neuronal apoptosis and brain damage caused by sepsis by maintaining BBB integrity and inhibiting neuroinflammation and oxidative stress. Its mechanism of action may be related to the activation of the Sirt1/ FoxO1 pathway and inhibition of NF-κB activation.