Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy highly dependent on Bruton\'s tyrosine kinase (BTK) signaling for survival and proliferation. While BTK inhibitors (BTKi) have markedly improved clinical outcomes, acquired resistance remains a major therapeutic challenge. Here, we show that CCS1477, a selective p300/CBP bromodomain inhibitor, overcomes BTKi resistance by disrupting a central epigenetic regulatory network in MCL. Building on CRISPR screening identifying p300 as a critical vulnerability in MCL, we found that CCS1477 significantly reduced viability and induced cell cycle arrest in both BTKi-sensitive and -resistant models. RNA-seq revealed that CCS1477 suppresses oncogenic pathways commonly hyperactivated in BTKi-resistant cells, including BCR, NF-κB, and PI3K/AKT signaling. CCS1477 also synergized with BTKi, further impairing resistant cell survival. Mechanistically, CUT&RUN and ATAC-seq profiling showed p300 inhibition induces global enhancer collapse, evidenced by reduced p300/H3K27ac occupancy and chromatin accessibility. Motif enrichment pinpointed PU.1 as a key partner of p300 and co-immunoprecipitation confirmed their interaction. Thus, p300 inhibition displaces PU.1 from enhancers and silences downstream transcriptional networks sustaining malignant B-cell survival. Overall, our findings identify that p300-PU.1 epigenetic axis as a central vulnerability in MCL and provide a mechanistic rationale for targeting p300 to overcome BTKi resistance.