Background: Sunitinib is an inhibitor of the multiple receptor tyrosine kinases (RTKs) for cancer therapy. Some sunitinib analogues could prevent neuronal death induced by various neurotoxins. However, the neuroprotective effects of sunitinib have not been reported. Methods: Cerebellar granule neurons (CGNs) and SH-SY5Y cells were exposed to low-potassium and MPP challenges, respectively. MTT assay, FDA/PI staining, Hoechst staining, DAF-FM, colorimetric nitric oxide synthase (NOS) activity assay, and Western blotting were applied to detect cell viability, NO production, NOS activity, and neuronal NOS (nNOS) expression. Short hairpin RNA was used to decrease nNOS expression. In vitro NOS enzyme activity assay was used to determine the direct inhibition of nNOS by sunitinib. Results: Sunitinib prevented low-potassium-induced neuronal apoptosis in CGNs and MPP-induced neuronal death in SH-SY5Y cells. However, PTK787, another RTK inhibitor, failed to decrease neurotoxicity in the same models. Sunitinib reversed the increase in NO levels, NOS activity, and nNOS expression induced by low potassium or MPP. Knockdown of nNOS expression partially abolished the neuroprotective effects of sunitinib. Moreover, sunitinib directly inhibited nNOS enzyme activity. Conclusions: Sunitinib exerts its neuroprotective effects by inhibiting NO overproduction, possibly via the inhibition of nNOS activity and the decrease in nNOS expression. © 2014 John Wiley & Sons Ltd.