SummaryOrganisms have homeostatic mechanisms to respond to cold temperature to ensure survival including the activation of the mammalian neuroprotective mild hypothermia response (MHR) at 32°C. We show activation of the MHR at euthermia by an FDA-approved medication Entacapone, proof-of-principle that the MHR can be medically manipulated. Utilizing a forward CRISPR-Cas9 mutagenesis screen, we identify the histone lysine methyltransferase SMYD5 as an epigenetic gatekeeper of the MHR. SMYD5 represses the key MHR geneSP1at euthermia but not at 32°C. This repression is mirrored by temperature-dependent levels of H3K36me3 at theSP1-locus and globally indicating that the mammalian MHR is regulated at the level of histone modifications. We identified 45 additional SMYD5-temperature dependent genes suggesting a broader MHR-related role for SMYD5. Our study provides an example of how the epigenetic machinery integrates environmental cues into the genetic circuitry of mammalian cells and suggests novel therapeutic avenues for neuroprotection after catastrophic events.