Neuroprotective actions of scatter factor/hepatocyte growth factor (SF/HGF) have not been described. We examined the effects of SF/HGF in comparison to acidic fibroblast growth factor‐1 (FGF‐1) on N‐methyl‐d‐aspartate (NMDA) and quinolinic acid (QUIN)‐induced excitotoxicity in primary cerebellar granule neurons. Exposure to NMDA or QUIN for 24 h resulted in concentration‐dependent cell death (p < 0.001) that was completely attenuated (p < 0.001) by pre‐treatment of cells with SF/HGF (50 ng/mL) or FGF‐1 (40 ng/mL). SF/HGF and FGF‐1 activated both Akt and MAP‐kinase > threefold (p < 0.001). Neither SF/HGF nor FGF‐1 activated cyclic AMP‐response element binding protein (CREB), a downstream target of MAP‐kinase, whereas brain‐derived neurotrophic factor (BDNF) activated both MAP‐kinase and CREB in granule neurons. Neuroprotection against NMDA or QUIN by SF/HGF and FGF‐1 was negated by the addition of LY294002 (10 µm) or wortmannin (100 nm), two distinct inhibitors of phosphatidylinositol 3‐kinase (PI3‐K), but not by the MAP‐kinase kinase (MEK) inhibitor PD98059 (33 µm). Likewise, expression of a dominant‐negative mutant of Akt (Akt‐kd) completely prevented the neuroprotective actions of SF/HGF and FGF‐1. Overexpression of a constitutively activated Akt (Akt‐myr) or wild‐type Akt (wtAkt) attenuated excitotoxic cell death. These data show that both SF/HGF and FGF‐1 protect cerebellar granule neurons against excitotoxicity with similar potency in a PI3‐K/Akt‐dependent and MAP‐kinase/CREB‐independent manner.