Non-small cell lung cancer (NSCLC) is a prevalent and lethal form of lung cancer with few effective treatment options, and targeted therapies for PI3K–mutated NSCLC remain particularly limited. The phosphatidylinositol 3-kinase (PI3K) pathway, frequently activated in NSCLC, is a viable therapeutic target, especially in tumors harboring PI3K mutations. Alpelisib (BYL719), a selective PI3Kα inhibitor, has shown promise, but its efficacy is often hampered by compensatory survival mechanisms, including autophagy. This study assesses the therapeutic potential of alpelisib as a monotherapy and in combination with an autophagy inhibitor for PI3K–mutated NSCLC. Alpelisib significantly reduced cell viability in human NSCLC cell lines in a dose- and time-dependent manner, with enhanced markers of autophagy and apoptosis, with pronounced effects in PI3K–mutant H460 cells. Co-treatment with alpelisib and chloroquine (CQ) further suppressed tumor cell growth, viability, migration, and colony formation more effectively than alpelisib alone, owing to increased apoptosis, elevated early and late apoptotic populations, and increased levels of cleaved PARP and caspase-3. In xenograft mouse models, the combination of alpelisib and CQ significantly inhibited tumor growth and reduced EGFR-Ras signaling compared to monotherapy. These findings suggest that combining alpelisib with autophagy inhibition significantly enhances its antitumor activity in PI3K–mutated NSCLC, highlighting a promising therapeutic strategy to address unmet clinical needs in this molecular subset. This discovery opens new possibilities for developing innovative targeted therapies for challenging NSCLC.