Transformed follicular lymphoma (t-FL) is an aggressive and heterogeneous hematological malignancy with limited treatment success; the development of novel therapeutic approaches is urgently needed for patients with t-FL. Here, we conducted high-throughput screening (HTS) and in vitro experiments using t-FL cell lines and primary samples to assess the synergistic effects of the histone deacetylase inhibitor chidamide and the BCL-2 inhibitor venetoclax. In vivo efficacy was further tested in xenograft models. The combination of venetoclax and chidamide significantly inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in the G0/G1 phase across multiple t-FL cell lines. Furthermore, the combined therapy effectively reduced tumor burden, extended overall survival in xenograft models, and synergistically targeted patient samples, while sparing normal PBMCs. Mechanistically, this combination disrupted mitochondrial membrane potential and modulated the Wnt signaling pathway, as evidenced by decreased protein expression levels of Wnt3a, Wnt5a/b, β-catenin, and phosphorylated GSK3β. Concurrently, the combined regimen enhanced their respective anticancer effects by inhibiting the key genes HDAC10 and BCL-xL. Taken together, venetoclax combined with chidamide presents a potent anticancer strategy in preclinical models of t-FL and merits further exploration in clinical trials to validate its effectiveness and safety for treating t-FL.