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Background: Although many studies have defined mechanisms of resistance to EGFR‐TKIs, acquired resistance remains the major limitation of monotherapy with EGFR‐TKIs. Methods: Cell viability was analyzed using a Cell Counting Kit‐8 (CCK‐8) assay. EGFR T790M mutation was sequenced on a HiSeq 4000 platform. mRNAs from HCC827 and HCC827 gefitinib‐resistant (GR) cells were analyzed by genome analyzer‐based deep sequencing. The effect of anlotinib on apoptosis and cell cycle arrest of HCC827 GR was detected by fluorescence‐activated cell sorting (FACS) analysis. A mouse xenograft model was used to assess the effect of anlotinib on HCC827 GR cells. Results: The T790M mutation was found in the PC‐9 GR cell line but not in the HCC827 GR cell line. Anlotinib could suppress the growth of HCC827 GR cells by inhibiting FGFR1 in vitro and in a mouse xenograft model. Moreover, FGFR1 was overexpressed in HCC827 GR cells, and the knockdown of FGFR1 reversed gefitinib resistance in HCC827 GR cells. Furthermore, anlotinib induced apoptosis and cell cycle arrest in HCC827 GR cells by increasing the activity of Caspase‐3. Conclusions: FGFR1 overexpression could be the mechanism of EGFR‐TKI acquired resistance and anlotinib can suppresse the growth of EGFR‐TKI‐resistant NSCLC cells without T790M mutation. [ABSTRACT FROM AUTHOR]