Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3, encoded byKMT2C) histone methyltransferase occur in a range of solid tumors, and heterozygous deletions encompassingKMT2Coccur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here, we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating theCdkn2atumor suppressor locus. Disruption ofKmt2ccooperates withMycoverexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to theCdkn2alocus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded tumor suppressors p16/Ink4a and p19/Arf. Conversely, elevatedKMT2Cexpression increases its binding to theCDKN2Alocus and co-activates gene transcription. EndogenousKmt2crestoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations inKMT2CandCDKN2Awere associated with similar transcriptional profiles in human HCC samples. These results collectively point to a new mechanism for disruptingCDKN2Aactivity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network.