This study reveals a previously undiscovered role of suppression of TRPM2, an important regulator of Ca2+ influx, in mediating therapeutic efficacy of osimertinib against EGFR mutant non‐small cell lung cancer and suggests targeting TRPM2 as a potentially promising strategy for managing acquired resistance to osimertinib and other third generation EGFR inhibitors. Here, EGFR is linked to lung cancer.