Background: S-CAV is a natural monoterpene that possesses antioxidant, anti-inflammatory, and anticancer activities. Both HIF and NF-κB pathways play a role in the hypoxia and inflammation during cancer progression. Objectives: In this study, we determine the effect of S-CAV against hypoxia-induced by CoCl₂ on A549 cells through the relationship between HIF-1α and NF-κB as well as inflammatory cytokines and oxidative stress. Methods: A549 cells were treated with S-CVN and CoCl₂ either alone or in combination for 24 hours. Afterward, cytotoxicity, cell viability, and mode of cell death were determined. Different markers were measured to detect the effect of S-CVN on CoCl₂ induced oxidative damage (MDA and TAC), hypoxia associated inflammation (IL-6 and TNF-α), as well as HIF-1α and NF-κB gene expression. Results: The results showed that S-CAV and CoCl₂ induced cytotoxicity at concentrations 4 and 6.2 mM. S-CAV and CoCl₂ combination therapy showed apoptotic cell death and a reduction in oxidative stress markers. Moreover, S-CAV in combination therapy downregulates the mRNA HIF-1α and NF-κB expression that parallels the reduction in IL-6 and TNF-α levels. Conclusion: Therefore, S-CAV possesses an antihypoxic effect on A549 CoCl₂ treated cells by reducing the oxidative stress, HIF-1α, and NF-κB gene expression as well as proinflammatory cytokines.