Accumulating evidence suggests that high expression of FGFR1 is closely related to the development of lung cancer especially in non-small cell lung cancers (NSCLC), to which non-ATP competitive inhibitors represent an effective therapeutical approach due to their good specificity. Herein, a series of NDGA analogues with the framework of bisaryl-1,4-dien-3-one as novel FGFR1 inhibitors have been designed and screened. Among them Aea4 and Aea25 showed strong FGFR1`inhibition and high selectivity over other receptor kinases. The kinase inhibitory assay in different ATP concentrations and computer-assistant molecular docking showed that the FGFR1 inhibition mode of both Aea4 and Aea25 was non-ATP-competitive. The in vitro and in vivo study on anticancer efficacy of Aea4 and Aea25 against non-small cell lung cancer involves inhibition of cell proliferation, apoptosis induction and cell cycle arrest with no toxicity. Thus, these two novel non-ATP competitive inhibitors derived from NDGA may have a great therapeutic potential in the treatment of NSCLC. This work also provides a structural lead for the design of new non-ATP-competitive FGFR1 inhibitors.