Background and Purpose: EGFR targeted therapy has pioneered a new era of NSCLC treatment. However, drug resistance is the major challenge of such therapy. Osimertinib is the latest generation of EGFR inhibitor and is clinically used for the treatment of NSCLC patients harboring EGFRT790M gatekeeper mutations. Unfortunately, the patients treated with Osimertinib also developes resistance and no follow-up drugs are currently available in clinic. EGFRC797S triple mutations have been identified as the pivotal causes contributing to Osimertinib resistance. This study aims to identify novel EGFR inhibitors that can target EGFRC797S triple mutations and conquer Osimertinib resistance through drug repurposing. Experimental Approach: Osimertinib-resistant NSCLC cell models were constructed by lentiviral transfection in PC-9 cell line and used for drug repurposing screen. The hit compound was further confirmed by kinase inhibition assay, immunoblot, and molecular docking. Then cell cycle, proliferation, and apoptosis were detected after hit treatment. The in vivo anti-NSCLC effect of the hit was also evaluated in the resistant xenografts. Key Results: We successfully established Osimertinib-resistant NSCLC cell lines harboring EGFRdel19/T790M/C797S or EGFRL858R/T790M/C797S mutation and identified the LRRK2 inhibitor CZC54252 to be an effective inhibitor against EGFRC797S triple mutations. CZC54252 could potently restrain the growth of NSCLC cells resistant to Osimertinib both in vitro and in vivo by directly targeting EGFR resistant mutations instead of its original targets. Conclusion and Implications: Overall, the repurposing of CZC54252 in inhibiting EGFRC797S triple mutations and conquering Osimertinib resistance lays a chemical foundation for the research and development of novel next-generation EGFR inhibitors.