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Cancer patients who initially benefit from Erlotinib, a drug targeting EGFR path, eventually develop resistance to the drug. The underlying mechanism is largely unknown. This study investigated the role of ARL4C in Erlotinib resistance development of NSCLC. qRT-PCR and Western blotting were performed to analyze the expression of mRNA and protein of ARL4C in two NSCLC cell lines (HCC827 and PC-9). Several assays (MTS, colony formation, transwell migration, luciferase reporter, and chromatin-immunoprecipitation) were used to explore the role of ARL4C in biofunctional changes of Erlotinib-resistant cells and their associations with Jak2/Stat 5/ β -catenin signaling. Results demonstrated that (1) long-term use of Erlotinib resulted in downregulation of ARL4C ; (2) overexpression of ARL4C could regain the sensitivity to Erlotinib in the drug-resistant HCC827/ER cells, while downregulation of ARL4C increased HCC827, and PC-9 cells' resistance to the drug; (3) Erlotinib-induced downregulation of ARL4C resulted in phosphorylation of Jak2/Stat5 and upregulation of β -catenin and their related molecules Axin2, CD44, Ccnd1, Lgr-5 , and MMP7 , which promoted the malignant behaviors of Erlotinib-resistant cells; (4) chromatin immunoprecipitation and luciferase reporter assay revealed that Stat5 could bind to β -catenin promoter to upregulate molecules to maintain the malignant behaviors, which might count for how Erlotinib-resistant cell survived while EGFR path was blocked; (5) the expression of ARL4C was not associated with known EGFR gene mutations in both Erlotinib-resistant cells and NSCLC tissues. Our data suggest that Erlotinib resistance of NSCLCs is associated with downregulation of ARL4C via affecting Jak/Stat/ β -catenin signaling. ARL4C could serve as a biomarker to predict the effectiveness of TKI targeting therapy and a potential therapeutic target for overcoming Erlotinib resistance in NSCLC. [ABSTRACT FROM AUTHOR]