This chapter provides a comprehensive review of the current evidence regarding the use of metformin for preventing ovarian hyperstimulation syndrome (OHSS) in assisted reproductive technology (ART) cycles. Metformin, an oral biguanide widely used as an insulin sensitizer, has been extensively studied in the context of polycystic ovary syndrome (PCOS). We examine the biological rationale behind metformin’s potential effectiveness in mitigating OHSS risk through its role in insulin signaling pathways, AMPK inhibition, and reduction of ovarian hyperandrogenism. The chapter critically evaluates the evolving evidence from randomized trials over the past two decades, highlighting the initial promising results in GnRH agonist protocols that led to recommendations by some international societies. However, more recent studies with GnRH antagonist protocols, which have become standard practice and significantly reduced OHSS incidence independently, have not consistently demonstrated benefits from metformin administration. We also discuss emerging alternatives such as myoinositol and their comparative efficacy. Current international guidelines offer divergent recommendations on metformin use for OHSS prevention, reflecting the need for additional high-quality research. This review concludes that while metformin may still benefit select PCOS patients in improving ovulation frequency and pregnancy outcomes, clinical interventions such as GnRH agonist triggering and freeze-all strategies have largely superseded pharmacological prevention of OHSS in modern ART practice.