PI3K delta and HDAC6 inhibitors play important roles in the treatment of lymphoma. Herein, a novel series of purinebased PI3K delta/HDAC6 dual inhibitors have been rationally designed and synthesized by incorporating an HDAC pharmacophore into our previously reported PI3K delta inhibitor scaffold. Structure-activity relationship (SAR) studies led to the discovery of the lead compound 22E, which showed potent inhibitory activity towards PI3K delta and HDAC6, with IC50 values of 2.4 nM and 6.2 nM, respectively. Compound 22E showed significantly enhanced antiproliferative activities against multiple non-Hodgkin's lymphoma (NHL) cells compared with either selective PI3K delta inhibitor or HDAC6 inhibitor, with IC50 values of 34 nM and 53 nM against SU-DHL-6 and JEKO-1 cells, respectively. Subsequent mechanistic studies revealed that compound 22E effectively arrested the cell cycle in the G0/G1 phase and induced cell apoptosis in SU-DHL-6 and JEKO-1 cells. Meanwhile, 22E could simultaneously block the PI3K/AKT/mTOR signaling pathway as well as increase the acetylation of alpha-tubulin and histone H3 levels. In addition, 22E prevented tumor growth in both SU-DHL-6 and JEKO-1 xenograft models, and there was no observable toxicity. These results demonstrated that 22E is a promising lead candidate with novel antitumor mechanism for the treatment of NHL.