Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders. Mounting studies have suggested an involvement of angiogenesis signaling in NHLs progression and resistance to treatment. In this study, we investigated the cytotoxicity of CS2164, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2 and Aurora B in NHL cells. By in vitro culture system and in vivo xenograft model, we found that CS2164 significantly inhibited cell growth and abolished clonogenicity in NHL cells in a dose- and time-dependent manner. Meanwhile, CS2164 significantly induced NHL cells apoptosis and cell cycle arrest in G0/G1 phase. Moreover, CS2164 suppressed NHL cells growth and progression in an in vivo xenograft model. Mechanistically, CS2164-induced cytotoxicity was closely associated with inhibition of VEGFR2 and Aurora B as well as their downstream signaling cascades, including P38, ERK and H3 pathways. In conclusion, CS2164 exerts its cytotoxic effect via inhibition of proliferation and induction of apoptosis by modulating VEGFR2 and Aurora B signaling pathway, supporting a potential role for CS2164 in the treatment of NHLs.