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Non-small cell lung cancer (NSCLC) has the highest incidence and mortality in the world. Aspirin has been reported to promote apoptosis, inhibit proliferation, stemness, angiogenesis, cancer-associated inflammation and migration in NSCLC. But the effect of aspirin on aerobic glycolysis in NSCLC is less reported. In the present study, we investigated whether aspirin blocked aerobic glycolysis of NSCLC cells to inhibit proliferation. Our results showed that aspirin inhibited viability, PCNA expression, ability of colony formation, dimished extracellular acidification rate (ECAR), oxygen consumption rate (OCR) and production of pyruvic acid and lactic acid, accompanied with reduced mitochondrial membrane potential (MMP), PGC-1α expression and ROS production, indicating mitochondrial dysfunction in NSCLC cells. AMPK and mitochondrial-localized deacetylase sirtuin 3 (SIRT3) were identified as the relevant molecular targets in glycolysis, but mechanism and relationship between AMPK and SIRT3 for aspirin induced glycolysis inhibition remain unknown in cancer cells. The investigation of underlying mechanism indicated that aspirin activated AMPK pathway to inhibit aerobic glycolysis and proliferation by upregulating SIRT3 after application of compound C (CC), an inhibitor of AMPK activity or SIRT3 siRNA. Upon activation of SIRT3, aspirin promoted the release of hexokinase-II (HK-II) from mitochondrial outer membrane to cytosol by deacetylating cyclophilin D (CypD). Consistently, aspirin significantly inhibited the growth of NSCLC xenografts and exhibited antitumor activity probably through AMPK/SIRT3/HK-II pathway in vivo. Collectively, AMPK/SIRT3/HK-II pathway plays a critical role in anticancer effects of aspirin, and our findings might serve as potential target for clinical practice and chemoprevention of aspirin in NSCLC. The proposed mechanism of aspirin on AMPK/SIRT3-mediated glycolysis in NSCLC cells. Aspirin upregulated SIRT3 by activating AMPK, then deacetylated CypD to cut down the binding between HK-II and VDAC1, promoted HK-II release from outer membrane of mitochondria into cytosol, finally blocked glycolysis in NSCLC cells. [Display omitted] [ABSTRACT FROM AUTHOR]