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Tyrosine kinase inhibitors are validated therapeutic agents against EGFR-mutated non-small cell lung cancer (NSCLC). However, the associated critical side effects of these agents are inevitable, demanding more specific and efficient targeting agents. Recently, we have developed and reported a non-covalent imidazo[1,2-<i>a</i>]quinoxaline-based EGFR inhibitor (<b>6b</b>), which showed promising inhibitory activity against the gefitinib-resistant H1975(L858R/T790M) lung cancer cell line. In the present study, we further explored the <b>6b</b> compound in vivo by employing the A549-induced xenograft model in nude mice. The results indicate that the administration of the <b>6b</b> compound significantly abolished the growth of the tumor in the A549 xenograft nude mice. Whereas the control mice bearing tumors displayed a declining trend in the survival curve, treatment with the <b>6b</b> compound improved the survival profile of mice. Moreover, the histological examination showed the cancer cell cytotoxicity of the <b>6b</b> compound was characterized by cytoplasmic destruction observed in the stained section of the tumor tissues of treated mice. The immunoblotting and qPCR results further signified that <b>6b</b> inhibited EGFR in tissue samples and consequently altered the downstream pathways mediated by EGFR, leading to a reduction in cancer growth. Therefore, the in vivo findings were in corroboration with the in vitro results, suggesting that <b>6b</b> possessed potential anticancer activity against EGFR-dependent lung cancer. <b>6b</b> also exhibited good stability in human and mouse liver microsomes.