Chromatin regulators are frequently mutated or aberrantly expressed in hepatocellular carcinoma (HCC), suggesting that the dysregulation of chromatin is a key feature driving liver cancer. In this study, using an epigenome-focused CRISPR screen in two-dimensional (2D) and three-dimensional (3D) conditions, we find the subunits of the menin-MLL1 complex to be among the strongest candidates for HCC survival. Inhibition of the menin-MLL1 interaction leads to global changes in occupancy of the complex with concomitant decreases in H3 lysine 4 trimethylation (H3K4me3), accessibility, and gene expression. Newly opened chromatin sites not bound by menin-MLL1 are associated with the recruitment of the pioneer transcription factor complex NF-Y yet remain embedded in silent chromatin domains, suggesting that they are primed for expression. A CRISPR-Cas9 screen of chromatin regulators in the presence of menin inhibitor SNDX-5613 reveals a significantly increased cell death when combined with NFYB knockout. Together, these data show that menin-MLL1 is necessary for HCC cell survival and cooperates with NF-Y to regulate oncogenic gene transcription.