BRD4, a member of the bromodomain and extraterminal domain (BET) family and an important epigenetic reader, has emerged as an attractive oncology target. Cholangiocarcinoma is a lethal neoplasm without approved targeted therapies. BET bromodomain inhibitors have shown promising effects in certain cancers including cholangiocarcinoma. Recently developed BRD4 Proteolysis Targeting Chimera (PROTAC) compounds lead to fast and efficient degradation of BRD4 and provides longer-lasting effect than small molecule BRD4 inhibitors. In this study, we investigated the antitumor effect of a newly developed BRD4 degrader ARV-825 in cholangiocarcinoma. Immunohistochemistry and Western blotting were used to determine the expression level of BRD4. CCK-8 assay and BrdU ELISA assay were used to assess cell proliferation. Caspase 3/7 activity and Annexin V/PI staining were used to assess apoptosis. We demonstrated that BRD4 expression was elevated in cholangiocarcinoma tissues compared to normal bile duct or surrounding normal liver tissues. ARV-825 produced fast and long-lasting loss of BRD4 protein, resulting in more inhibition of CCA cell proliferation and induction of apoptosis than BRD4 inhibitors OTX-015 and JQ1. C-Myc is a well-known downstream target of BRD4. We found that ARV-825 suppressed c-Myc levels more effectively than BRD4 inhibitors. However, ARV-825 did not inhibit c-Myc expression in CCA cells with low basal c-Myc levels. Further analysis showed that ARV-825 significantly upregulated p21 expression and arrested cell cycle progression at G1 phase. In conclusion, BRD4 degrader ARV-825 leads to rapid and sustained degradation of BRD4 and is effective against cholangiocarcinoma.