This dataset contains data-independent acquisition (DIA) proteomics data generated from K562 human leukemia cells treated with coffee extract or vehicle control. Quantitative proteomic analysis was performed to investigate molecular mechanisms underlying coffee-induced epigenetic remodeling. The proteomics dataset was integrated with histone modification profiling, ChIP-seq and RNA-seq analyses to characterize pathways associated with histone acetylation and MYC transcriptional regulation.