Background: Cerebral ischemia is caused due to insufficient blood flow to brain cells. This study evaluates the therapeutic effects of propionic acid (PA) on the abnormalities induced during the cerebral ischemic-reperfusion (CIR) injury in mice. Materials and Methods: CIR was induced by complete occlusion of the middle artery of the cerebrum for 15 min and reperfusion for 24 h in the experimental C57BL/6 mice. The analysis of mRNA levels of neuronal nitric oxide synthase (nNOS) was performed by reverse transcriptase polymerase chain reaction (RT-PCR). Inflammatory cytokines such as interleukin-6 (IL-6), IL-1 β, and tumor necrosis factor-alpha were quantitated by enzyme-linked immuno sorbent assay. Apoptosis-related proteins and nuclear factor-κB (NF-κB) were analyzed using Western blot technique. Results: PA demonstrated strong therapeutic effects on controlling the expression of nNOS that was analyzed using RT-PCR. Elevated levels of inflammatory cytokines, caspase-3, caspase-9, and phosphorylated NF-κB during cerebral ischemia were significantly controlled during PA treatment. Conclusion: Our findings demonstrated that PA through oral gavage exhibited healthier effects on the damage caused due to CIR injury.