Aberrant activation of EGFR drives the progression of non-small-cell lung cancer (NSCLC). As one of the most prevalent driver genes in NSCLC, EGFR represents a critical therapeutic target for patients with NSCLC. In this study, we synthesized 2,4-pyrimidinediamine derivative ZX-3. Compared to its lead compound ceritinib, which has weak cytotoxicity for EGFR-driven NSCLC, ZX-3 exhibited potent cytotoxicity against EGFR-driven NSCLC. We further investigated the antitumor activity and mechanisms of ZX-3 both in vitro and in vivo. Through high-throughput target screening using RTK protein arrays and surface plasmon resonance (SPR) assays, it was demonstrated that ZX-3 reversibly targets the EGFR protein and inhibits its downstream PI3K/AKT signaling pathway. In vitro experiments revealed that ZX-3 suppresses cell colony formation in H2228 cells, induces G1-phase cell cycle arrest, and promotes apoptosis. In in vivo xenograft studies, ZX-3 treatment significantly suppressed tumor growth without obvious toxicity. Collectively, ZX-3 represents a reversible EGFR inhibitor based on borylation modification and possesses favorable antitumor activity both in vitro and in vivo, offering a novel strategy for the subsequent development of EGFR-targeted inhibitors.