Ischemic stroke is a high mortality disease that causes irreversible damage. Chlorogenic acid is a polyphenolic substance with neuroprotective properties. Bcl-2 family proteins perform a critical role in apoptosis process. Bcl-2 and Bcl-xL are anti-apoptotic proteins that prevent cell death, and Bax and Bad are pro-apoptotic proteins that promote apoptosis. We investigated whether chlorogenic acid modulates Bcl-2 family proteins during focal cerebral ischemia. We made a rat model of ischemic stroke by performing middle cerebral artery occlusion (MCAO). Chlorogenic acid (30 mg/kg) or phosphate-buffered saline was treated via intraperitoneal injection 2 hr before MCAO. Neurological behavioral tests were performed 24 hr after MCAO damage and cortical tissues were collected. Reverse transcription-PCR, Western blot, and immunofluorescence staining were performed to observe changes in Bcl-2 family proteins expression. MCAO-damage induced neurobehavioral disorders and chlorogenic acid alleviate these deficits. Bcl-2 and Bcl-xL expressions were decreased and Bax and Bad expressions were increased in MCAO animals. However, chlorogenic acid treatment attenuated the decrease of Bcl-2 and Bcl-xL and the increase of Bad and Bax due to MCAO surgery. Moreover, chlorogenic acid treatment attenuated MCAO-induced upregulation of caspase-3. These findings suggest that chlorogenic acid exerts neuroprotective effects against MCAO damage by regulating Bcl-2 family proteins including Bcl-2, Bcl-xL, Bax, and Bad.