Metastasis is the main cause of tumor-related mortality in breast cancer patients; therefore, advancing our understanding of the metastatic cascade is imperative to improve patient outcomes. Prior research indicates cancer cells with increased metastatic potential have acquired adaptive properties induced by both tumor intrinsic factors and extrinsic factors in the tumor microenvironment (TME), including hypoxia. The cellular mechanisms that enable adaption and survival to low oxygen during normal developmental processes are often hijacked by cancer cells as their rapid proliferation and irregular angiogenesis produce regions of hypoxia within the TME, which has been extensively examined in its association with tumor progression. However, previous hypoxia research has been primarily focused on signaling changes that occur when cancer cells are in the hypoxic TME and does not account for long-term changes that may occur once cancer cells re-enter normoxia, such as when they enter circulation as circulating tumor cells (CTC) and metastasize. In this study, we analyze the lasting effects of hypoxia in luminal breast cancer cells and investigate their clinical impact. RNA-Sequencing of luminal breast cancer cell lines indicates a broad transcriptional hypoxic memory is maintained in post-hypoxic cells. Functional assays to measure well-established hypoxic-mediated phenotypes including metabolic reprogramming, proliferation, migration, chemotherapy resistance, and CTC clustering reveals that these post-hypoxic cells also maintain certain pro-metastatic phenotypes after reoxygenation. Additionally, we established a highly prognostic hypoxic memory metagene signature that was validated in vivo. This hypoxic memory signature is associated with more aggressive tumor characteristics in estrogen receptor-positive (ER+) patients and has greater prognostic potential compared to hypoxic-specific metagene signatures. Moreover, relapse free survival data suggests the hypoxic memory signature may be predictive of patient responses to chemotherapy in ER+ patients, which was further supported by the observed resistance to capecitabine in luminal breast cancer cell lines in vitro. This hypoxic memory signature could provide a novel biomarker for long-term hypoxic burden and patient outcomes in ER+ breast cancer patients.