The mechanism for the earliest response of central neurons to hypoxia—an increase in voltage-gated sodium current (I_Na)—has been unknown. Here, we show that hypoxia activates the Small Ubiquitin-like Modifier (SUMO) pathway in rat cerebellar granule neurons (CGN) and that SUMOylation of NaV1.2 channels increases I_Na. The time-course for SUMOylation of single Na_V1.2 channels at the cell surface and changes in I_Na coincide, and both are prevented by mutation of Na_V1.2-Lys38 or application of a deSUMOylating enzyme. Within 40 s, hypoxia-induced linkage of SUMO1 to the channels is complete, shifting the voltage-dependence of channel activation so that depolarizing steps evoke larger sodium currents. Given the recognized role of I_Na in hypoxic brain damage, the SUMO pathway and Na_V1.2 are identified as potential targets for neuroprotective interventions.