In the current research, neuroprotection and performance improvement have been investigated in MCAO animal model treated with exosomes combined with rt-PA. Middle cerebral artery occlusion (MCAO) was induced in 25 adult male Wistar rats. Rats received rt-PA with a dose of 100 µg/kg in a single dose or drived-exosome from bone marrow MSCs. The Garcia scoring system and elevated body test were employed as behavioral tests for the functional recovery assessment. Cresyl violet staining was applied to evaluate the cell death degree in brain tissues. Immunohistochemical analysis was performed for the detection of GFAP and IBA1-positive cells. Results Cresyl violet staining revealed that the population of dark cells was significantly reduced in all treatment groups. A considerable increase (P ≤ 0.05) in catalase enzyme was observed in the combination therapy group compared whit the MCAO group (P ≤ 0.05). The amount of GPX despite the increase in all treatment groups compared to MCAO group was not statistically significant (P ≥ 0.05). Our conclusion was approved by the Nlrp1 and Nlrp3 downregulation during combination therapy in MCAO model by reduction in cell death rate. The Density of GFAP-positive cells Showed a decrease in the exosome with or without rt-PA experimental groups in comparison with the MCAO group (P < 0.05). Our observation indicated that exosomes, in combination with rt-PA, resulted in the noticeable functional recovery, neuronal regeneration, and reduction of neuronal cell death after a 7-day period of the MCAO induction. This novel therapeutic strategy could provide a better treatment option for those patients suffered from stroke.