Non-small cell lung cancer (NSCLC) remains deadly, indicating a need for better diagnosis and treatment strategies. The protein OVOL2 is known to suppress tumor development in NSCLC and other cancers. However, it’s unclear whether OVOL2 exerts its anticancer effects by disrupting aerobic glycolysis, the main energy pathway in tumor cells. To find out, researchers recently investigated OVOL2 signaling in NSCLC. OVOL2 was downregulated in NSCLC cells and mouse NSCLC tissues compared to normal lung (NL) samples. Specifically, OVOL2 was negatively regulated by NF-κB signaling via the ubiquitin–proteasome degradation pathway. However, lentivirus (LV)-mediated overexpression of OVOL2 reduced NSCLC cell survival in vitro, and OVOL2 impaired aerobic glycolysis in NSCLC cell lines and mouse xenograft models. OVOL2 exerted its beneficial effects by binding to P65 and inhibiting P300 recruitment while facilitating HDAC1–P65 binding. These interactions negatively regulated the NF-κB pathway to suppress translocation of the glucose transporter GLUT1 to the cell membrane, thus inhibiting glucose import into the tumor cells. Although further clarification is needed, this work identifies a regulatory circuit between OVOL2 and NF-κB that affects glucose metabolism in NSCLC and provides potential targets for future NSCLC treatment.