The cellular and tissue response to acute hypoxia is mediated by a complex adaptive response initiated by hypoxia-inducible factors (HIF) 1 and 2. HIF proteins are key transcription factors that modulate gene expression to adapt cells to the low oxygen tension. Cellular studies of hypoxia have used the low oxygen model by using hypoxia chambers to monitor the gene expression changes, while others have utilized hypoxia mimetics in normoxic conditions. Here, we provide a comparison of the utility and limitations of two hypoxia mimetics by studying the changes in the miRNA and mRNA expression profiles compared to the low oxygen model. We utilized data from NGS-based global analyses, qPCR validation, and HIFa silencing experiments to determine the distinct profiles of HIF-1 and HIF-2 activities of the hypoxia and mimetic models. The ability of CoCl₂ and DMOG (dimethyloxalylglycine) to mimic hypoxia was tested in cultured human endothelial cells. The results demonstrated that their treatments resulted in a differential stabilization of HIF-1α and HIF-2α, with CoCl₂ predominantly stabilizing HIF-1α, and DMOG stabilizing HIF-2α. While CoCl₂ and DMOG show potential in mimicking certain isoform-specific effects, their inability to completely mimic their effects on miRNAs and their mRNA targets reveals that these changes do not fully reproduce the hypoxia-induced effects in pathways related to angiogenesis and apoptosis. Taken together, while the hypoxia mimetics offer valuable insights into the isoform-specific effects of HIF-1 and HIF-2, their inability to fully replicate the complexity of hypoxia-induced miRNA interactions is not illustrated in human endothelial cells.