Hypoxia is a key microenvironmental factor shaping tumor cell survival and plasticity, but its cellular consequences depend on the cancer subtype. Here, we compare breast cancer cell lines with varying metastatic potential (MP) in response to CoCl₂-induced hypoxia (100 μM, 20 h), analyzing the results immediately (T0) and after 24 h (T1). Plasma membrane damage was measured by the number of propidium iodide-positive cells. Hypoxia pathway activation was evaluated using HIF-1α immunofluorescence, while phenotypic changes were assessed through quantitative morphometric analysis. Chemically induced hypoxia promoted a delayed increase in membrane failure in low-MP cells, consistent with reduced tolerance to hypoxia-mimetic stress. In contrast, high-MP cultures showed a lower PI-positive fraction at T1, consistent with enhanced survival under these conditions. This divergence was accompanied by higher basal and hypoxia-induced HIF-1α levels in high-MP cells. High-MP cells uniquely demonstrated delayed shape changes after exposure to hypoxia-mimetic conditions, evolving into a more compact and rounded form, suggesting phenotypic plasticity instead of structural deterioration. Together, our findings provide insight into how oxygen deprivation impacts cell destiny and phenotypic plasticity in breast cancer models with varying metastatic risks.