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The PI3K pathway and epigenetic regulation have been shown to play a pivotal role in the development and progression of diffuse large B-cell lymphoma (DLBCL). In the clinic, existing PI3K and HDAC inhibitors show limited efficacy as single agents toward DLBCL. However, in preclinical studies, the synergistic effects of PI3K inhibitors and HDAC inhibitors on DLBCL have sparked the enthusiasm of researchers to target both PI3K and HDAC. We hypothesized that a novel dual PI3K/HDAC inhibitor, BEBT-908, would display improved pharmacologic effects on DLBCL. We analyzed the anti-DLBCL activity of BEBT-908 in a comprehensive manner, demonstrating its role in the suppression of in vitro cell proliferation, blockade of PI3K and HDAC activities, inhibition of multiple signaling pathways, and promotion of apoptosis and cell cycle arrest. BEBT-908 showed potent PI3K/HDAC inhibition, with nanomolar IC50 values against DLBCL cell lines. Moreover, BEBT-908 inhibited multiple pathways, including JAK/STAT3, MAPK/ERK and NF-κB, and induced apoptosis and cell cycle arrest at G1 phase in these cells. Additionally, dual PI3K/HDAC inhibition was superior to the inhibition of PI3K or HDAC alone. The dual inhibitor BEBT-908 is a promising lead compound for developing novel targeted therapeutic agents against DLBCL.