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Simple Summary: NSCLC is one of the most life-threatening forms of oncological diseases. Although targeted and immunotherapy treatments have improved NSCLC prognosis, the chance of surviving is still limited for many patients. Therefore, further efforts are required to improve NSCLC care. AdipoRon is emerging as an antineoplastic molecule in the treatment of different cancers, but its potential in NSCLC is yet to be explored. Herein, we demonstrated that AdipoRon strongly impairs viability, growth and stemness in NSCLC cells. We also recorded higher glucose consumption and lactate accumulation as a result of AdipoRon treatment. Remarkably, the employment of glycolytic-interfering agents enhanced its antiproliferative features. A signaling pathways analysis revealed a marked AMPK phosphorylation, while, in contrast, its abrogation by Compound-C significantly counteracted AdipoRon effectiveness. Altogether, these findings emphasize AdipoRon's anticancer feature even in NSCLC, supporting its endorsement as a future candidate in cancer and NSCLC therapy. Despite the countless therapeutic advances achieved over the years, non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. To this primacy contribute both non-oncogene addicted and advanced NSCLCs, in which conventional therapies are only partially effective. The adiponectin receptor agonist AdipoRon has revealed antiproliferative action in different cancers, including osteosarcoma and pancreatic cancer. Herein, we investigated its potential anticancer role in NSCLC for the first time. We proved that AdipoRon strongly inhibits viability, growth and colony formation in H1299 and A549 NSCLC cells, mainly through a slowdown in cell cycle progression. Along with the biological behaviors, a metabolic switching was observed after AdipoRon administration in NSCLC cells, consisting of higher glucose consumption and lactate accumulation. Remarkably, both 2-Deoxy Glucose and Oxamate glycolytic-interfering agents greatly enhanced AdipoRon's antiproliferative features. As a master regulator of cell metabolism, AMP-activated protein kinase (AMPK) was activated by AdipoRon. Notably, the ablation of AdipoRon-induced AMPK phosphorylation by Compound-C significantly counteracted its effectiveness. However, the engagement of other pathways should be investigated afterwards. With a focus on NSCLC, our findings further support the ability of AdipoRon in acting as an anticancer molecule, driving its endorsement as a future candidate in NSCLC therapy. [ABSTRACT FROM AUTHOR]