Gefitinib, an epidermal growth factor receptor (EGFR)‑specific drug, is effective for ~1 year, after which resistance is inevitable. Calpain 2 (CAPN2) is known to serve a role in the drug response and resistance in certain cancer therapies. However, the full function of CAPN2, particularly in non‑small cell lung cancer, has not yet been elucidated. In the present study, CAPN2 expression in gefitinib‑resistant lung adenocarcinoma cells was investigated. CAPN2 function in these cells was further evaluated using gene knockdown both in vitro and in vivo. The results demonstrated that CAPN2 was strongly associated with gefitinib‑resistance, and CAPN2 mRNA and protein expression levels were significantly increased in gefitinib‑resistant cell lines. Furthermore, CAPN2 knockdown inhibited gefitinib‑resistant cell proliferation in vitro and in vivo. CAPN2 conferred gefitinib‑resistance by inhibiting cell apoptosis and arresting the cell cycle. CAPN2 knockdown also induced caspase activation and mitochondrial dysfunction, and its function in gefitinib resistance appeared to be largely mediated by EGFR/protein kinase B/survivin signaling pathway activation. These results suggest that CAPN2 is responsible for EGFR‑tyrosine kinase inhibitor resistance, and CAPN2 inhibition may be used to provide therapeutic benefits in the treatment of gefitinib resistance.