HDAC4 is a Class II histone deacetylase (HDAC) that is highly expressed in the brain, but whose functional significance in the brain is not known. We show that forced expression of HDAC4 in cerebellar granule neurons protects them against low potassium‐induced apoptosis. HDAC4 also protects HT22 neuroblastoma cells from death induced by oxidative stress. HDAC4‐mediated neuroprotection does not require its HDAC catalytic domain and cannot be inhibited by chemical inhibitors of HDACs. Neuroprotection by HDAC4 also does not require the Raf‐MEK‐ERK or the PI‐3 kinase‐Akt signaling pathways and occurs despite the activation of c‐jun, an event that is generally believed to condemn neurons to die. The protective action of HDAC4 occurs in the nucleus and is mediated by a region that contains the nuclear localization signal. HDAC4 inhibits the activity of cyclin‐dependent kinase‐1 (CDK1) and the progression of proliferating HEK293T and HT22 cells through the cell cycle. Mice‐lacking HDAC4 have elevated CDK1 activity and display cerebellar abnormalities including a progressive loss of Purkinje neurons postnatally in posterior lobes. Surviving Purkinje neurons in these lobes have duplicated soma. Furthermore, large numbers of cells within these affected lobes incorporate BrdU, indicating cell‐cycle progression. These abnormalities along with the ability of HDAC4 to inhibit CDK1 and cell‐cycle progression in cultured cells suggest that neuroprotection by HDAC4 is mediated by preventing abortive cell‐cycle progression. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2008.