Ischemic neuronal injury is associated with several life- and vision-threatening diseases. Neuroprotection is essential in the treatment of these diseases. Here, we identified and characterized a novel peptide, FK18, from basic fibroblast growth factor (bFGF). We further assessed the neuroprotective effects of this peptide and its potential mechanisms using the in vitro oxygen–glucose deprivation (OGD) model in SH-SY5Y cells and the in vivo retinal ischemia-reperfusion (I/R) injury model to mimic ischemic neuronal injury. Our results suggested that FK18 significantly increased the viability of and attenuated the apoptosis of SH-SY5Y cells. It also markedly alleviated I/R-induced retinal neuronal apoptosis, damage to retinal ganglion cells (RGCs), and morphological and functional damage to the retina. Moreover, FK18 increased Akt phosphorylation under both normoxic and OGD conditions, attenuated mitochondrial translocation of the proapoptotic protein Bad, up-regulated the expression of Bcl-2/Bax, and inhibited the release of cytochrome c from the mitochondria into the cytoplasm. These results suggested that FK18 is a novel neuroprotective agent that may serve as a prototype for neuroprotective drug development.