OBJECTIVES: This study aimed to explore the diagnostic, prognostic, and therapeutic values of cadherin family genes (CDH1, CDH2, and CDH3) in non-small cell lung cancer (NSCLC) subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). METHODOLOGY: We analyzed the expression of CDH1, CDH2, and CDH3 in LUAD and LUSC using TCGA and TIMER2 data, and evaluated protein levels through immunostaining data from the HPA database. Gene expression across LUAD and LUSC stages was examined using GEPIA2. Methylation and mutation analyses were conducted vby OncoDB and cBioPortal, respectively. Prognostic significance was assessed through survival analyses using the KM Plotter tool. Gene enrichment and immune infiltration correlations were investigated using DAVID and GSCA databases. Knockdown experiments in PC9 cells were performed to assess the effects of CDH1 and CDH2 on cell proliferation, colony formation, and wound healing. RESULTS: The expression of CDH1, CDH2, and CDH3 was significantly elevated in both LUAD and LUSC. Methylation analysis revealed reduced promoter methylation of cadherin genes in tumor samples compared to normal tissues. Mutational analysis showed that CDH2 exhibited the highest mutation frequency (63%), followed by CDH3 (23%) and CDH1 (19%). Survival analysis indicated that higher expression of CDH1, CDH2, and CDH3 was associated with poor prognosis in both LUAD and LUSC. Knockdown of CDH1 and CDH2 in PC9 cells resulted in reduced cell proliferation, colony formation, and impaired wound healing, with CDH2 knockdown showing more pronounced effects. CONCLUSION: CDH1, CDH2, and CDH3 were upregulated in LUAD and LUSC, contributing to tumor progression and poor prognosis. Knockdown of CDH1 and CDH2 in PC9 cells impaired proliferation, colony formation, and wound healing, highlighting their potential as therapeutic targets.