The present study aimed to develop novel hesperetin-loaded on multiple wall carbon nanotubes (Hst-MWCNTs) to resolve the restricted bioavailability of hesperetin (Hst) and to enhance its preventive effect on cerebral ischemia-reperfusion (I/R). The physicochemical characteristics of Hst-MWCNTs were evaluated by Fourier-transform infrared spectra (FT-IR) and field emission scanning electron microscopy (FE-SEM). Forty male Wistar rats were randomly divided into five groups (control, I/R, MWCNTs, Hst, and Hst-MWCNTs). Hst, MWCNTs and Hst-MWCNTs (15 mg/kg orally) were pretreated for 14 days, and then I/R was induced by bilateral common carotid artery occlusion (BCCAO). Learning and memory deficits were evaluated using the novel object recognition test (NORT). The percentage of infarct size, catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GRx), glutathione peroxidase (GPx) activities, malondialdehyde (MDA), and glutathione (GSH) levels was evaluated. Caspase-3 and Bcl-2 expressions were detected by qRT-PCR and Western blot analysis. Compared to the I/R group, Hst-MWCNTs considerably reduced learning and memory deficits, infarct size, and MDA levels. CAT, SOD, GRx, GPx activities and GSH levels were significantly increased in the Hst-MWCNTs group than in the I/R group. Additionally, Hst-MWCNTs significantly reduced the Caspase-3 expression but increased the Bcl-2 expression. All these results indicated that MWCNTs could be used as a promising novel carrier to enhance the oral bioavailability of Hst and to treat cerebral I/R injury.