Oxidative stress, inflammation and apoptotic neuronal cell death are cardinal mechanisms involved in the cascade of acute ischemic stroke. Lercanidipine apart from calcium channel blocking activity possesses anti-oxidant, anti-inflammatory and anti-apoptotic properties. In the present study, we investigated neuroprotective efficacy and therapeutic time window of lercanidipine in a 2 h middle cerebral artery occlusion (MCAo) model in male Wistar rats. The study design included: acute (pre-treatment and post-treatment) and sub-acute studies. In acute studies (pre-treatment) lercanidipine (0.25, 0.5 and 1 mg/kg, i.p.) was administered 60 min prior MCAo. The rats were assessed 24 h post-MCAo for neurological deficit score (NDS), motor deficit paradigms (grip test and rota rod) and cerebral infarction via 2,3,5-triphenyltetrazolium chloride (TTC) staining. The most effective dose was found to be at 0.5 mg/kg, i.p., which was considered for further studies. Regional cerebral blood flow (rCBF) was monitored till 120 min post-reperfusion to assess vasodilatory property of lercanidipine (0.5 mg/kg, i.p.) administered at two different time points: 60 min post-MCAo and 15 min post-reperfusion. In acute studies (post-treatment) lercanidipine (0.5 mg/kg, i.p.) was administered 15 min, 120 min and 240 min post-reperfusion. Based on NDS and cerebral infarction via TTC staining assessed 24 h post-MCAo, effectiveness was evident upto 120 min. For sub-acute studies same dose/vehicle was repeated for next 3 days and magnetic resonance imaging (MRI) was performed 96 h after the last dose. Biochemical markers estimated in rat brain cortex 24 h post-MCAo were oxidative stress (malondialdehyde, reduced glutathione, nitric oxide, superoxide dismutase), blood brain barrier damage (matrix metalloproteinases-2 and -9) and apoptotic (caspase-3 and -9). Lercanidipine significantly reduced NDS, motor deficits and cerebral infarction volume as compared to the control group. Lercanidipine (60 min post-MCAo) significantly increased rCBF (86%) as compared to vehicle treated MCAo group (64%) 120 min post-reperfusion, but failed to show vasodilatation with 15 min post-reperfusion group. Lercanidipine (13.78 ± 2.78%) significantly attenuated percentage infarct volume as evident from diffusion-weighted (DWI) and T2-weighted images as compared to vehicle treated MCAo group (25.90 ± 2.44%) investigated 96 h post-MCAo. The apparent diffusion coefficient (ADC) was also significantly improved in lercanidipine group as compared to control group. Biochemical alterations were significantly ameliorated by lercanidipine till 120 min post-reperfusion group and MMP-9 inhibition observed even with 240 min group. Thus, lercanidipine revealed significant neuroprotective effect mediated through attenuation of oxidative stress, inflammation and apoptosis.