Background: Lung cancer is one of the most common cancers and the leading cause of cancer-related death. Glycogen synthase kinase-3 (GSK-3) alpha, a member of the glycogen synthase kinase-3 family, reportedly plays a role in tumorigenesis. However, its biological function in tumorigenesis requires deeper exploration. Hypoxia is a major feature of solid tumor, along with decreasing availability of oxygen, inducing treatment resistance, and tumor progress. Methods: Levels of GSK3 alpha expression in clinical samples were detected using western blot and IHC assays, while its biological function and underlying mechanism of action in tumor progression were investigated using western blot, CCK8, cell cycle, colony formation, Transwell, ELISA and tube formation assays. Furthermore, we investigated the relationship between GSK3 alpha expression and the HIF1 alpha/VEGFA signaling pathway in vivo using a mouse xenograft model. Results: GSK3 alpha was significantly upregulated in NSCLC patients with cases that exhibited high GSK3 alpha levels recording shorter survival times. Moreover, GSK3 alpha overexpression promoted proliferation, migration, invasion and clone formation ability of NSCLC cells, while its silencing resulted in an opposite phenomenon. Moreover, GSK3 alpha not only activated the HIF1 alpha/VEGFA signaling pathway, but also regulated HIF1 alpha stabilization independently via the PHDs-pVHL signaling pathway. Moreover, GSK3 alpha-mediated tumor angiogenesis depended on HIF1 alpha expression both in vitro and in vivo. Conclusion: GSK3 alpha functioned as an oncogene in NSCLC tumorigenesis by regulating the HIF1/VEGFA signaling pathway in an independent manner through the PHDs-pVHL signaling pathway. These findings were expected to provide novel sights to guide future development of therapies for effective treatment of NSCLC.