Agents that inhibit bromodomain and extra-terminal domain (BET) protein have been actively tested in the clinic as potential anticancer drugs. Proteasome inhibitors such as carfilzomib (CFZ) are FDA-approved for the treatment of patients with advanced multiple myeloma and have been tested against other cancers. The current study focuses on the combination of a BET inhibitor (e.g., JQ1) and a proteasome inhibitor (e.g., CFZ) as a novel cancer therapeutic strategy and the underlying mechanisms. The tested combination (JQ1 with CFZ) synergistically decreased cell survival and enhanced apoptosis in vitro and inhibited tumor growth in vivo. The dramatic induction of apoptosis was accompanied by enhanced elevation of Bim and ER stress. Rim knockout significantly attenuated apoptosis induced by the combination, suggesting a critical role of Bim induction in mediating the enhanced induction of apoptosis by BET and proteasome co-inhibition. The combination significantly increased Rim mRNA levels with limited effect on Rim protein stability, suggesting a primary transcriptional regulation of enhanced Bim expression. Our findings warrant further investigation of this combinatorial strategy as an effective regimen against cancer in the clinic.