<p>Hypoxia-Inducible Factor-1α (HIF-1α) is a fundamental transcriptional regulator of cellular adaptation to low oxygen fluctuations and serves as a pivotal regulator of angiogenesis, metabolism, and steroidogenesis. Transient HIF-1α activation is indispensable for normal follicular growth, ovulation, and luteal formation, whereas sustained or dysregulated signalling contributes to aberrant angiogenesis, oxidative stress, and metabolic disturbances that typify polycystic ovary syndrome (PCOS) and other ovarian pathologies. The impaired HIF-1α signalling in the ovaries reduces the ability to adapt to the normal micro-hypoxic environment, which hinders the growth of follicles, leading to the follicular arrest. This contributes to the formation of cysts, resulting in polycystic ovaries. Due to its double role in ovarian physiology, HIF-1α is a potential therapeutic target. The various approaches, including minor molecule inhibitors and nanoparticle transfer systems, can inhibit HIF-1α activity, slowing down the symptoms of PCOS and infertility. This review critically summarises the current evidence on the role of HIF-1α in ovarian physiology and dysfunction. We integrate findings from human studies, in vivo models, and in vitro experiments to delineate how HIF-1α dysregulation contributes to ovarian pathology, with special focus on PCOS.</p>