Mantle cell lymphoma (MCL) is a rare and incurable subtype of non-Hodgkin lymphoma (NHL). Despite significant advancements in the treatments of MCL, the median overall survival 3-5 years after diagnosis. Bruton’s tyrosine kinase inhibitors (BTKi) have improved clinical outcomes in relapsed and refractory MCL patients and are now being adopted as first-line therapy. However, since acquired resistance to BTKi is inevitable, novel therapeutic strategies are required. Therefore, we evaluated that CCS1477 can overcome BKTi-resistance. CRISPR screening identified EP300 as a key vulnerability in MCL, highlighting its essential role in tumor growth and survival. EP300 knockout—distinct from its paralog CBP—significantly decreased viability of BTKi-resistant cells. Pharmacological inhibition of EP300 by CCS1477, a selective EP300/CBP bromodomain inhibitor, led to down-regulate BTK signaling and induce cell death in a dose-dependent manner. Furthermore, the combination of CCS1477 with BTKi exhibited significant synergistic effects in inhibiting BCR signaling and cell death. Given that previous studies have suggested that CCS1477 could regulate CD79B, a crucial component of BCR signaling, we confirmed that CCS1477 significantly reduced CD79B expression, thereby enhancing the responsiveness MCL to BTK inhibitors. In conclusion, these results suggest that targeting EP300 with CCS1477 may be a promising therapeutic approach for overcoming BTKi resistance in MCL.