Several cMET inhibitors have been developed as novel therapeutic candidates and are under investigation in clinical trials. New preclinical models to study mechanisms underlying resistance to these targeted agents are essential, as resistance acquired during treatment may lead to relapse. The squamous non-small-cell lung cancer (NSCLC) cell line EBC-1 harbors a cMET gene amplification and is sensitive to the cMET inhibitor crizotinib. Here, through multiple step selection with gradually increasing concentrations of crizotinib we established a resistant clone of these cells, termed EBC-CR. A tyrosine kinase activity assay did not show increased signaling of a bypassing pathway or renewed activity of cMET after crizotinib treatment. However, the pH-sensitive pHRodo Green AM probe showed increased acidification of the cytoplasm and lysosomes of EBC-CR cells. Live cell fluorescence imaging also showed an increase in lysosomal number after crizotinib treatment, and the intracellular concentration of crizotinib was significantly lower in crizotinib-resistant EBC-CR cells as compared to the drug sensitive parental EBC-1 cells. These findings suggest that the impaired accumulation of crizotinib in EBC-CR cells, together with the increased acidification of the lysosomes, contributes to crizotinib resistance in cMET-amplified NSCLC cells. In conclusion, the present research identified a novel mechanism used by cancer cells to confer resistance to cMET inhibition. These results prompt future studies for the establishment of innovative therapeutic strategies to overcome resistance to cMET kinase inhibitors by modulation of lysosomal acidification.