<p>Pregnancy-related disorders, including preterm birth, preeclampsia, recurrent spontaneous abortion, and fetal growth restriction, represent major contributors to global maternal and infant morbidity and mortality. Their pathophysiology involves complex mechanisms such as immune dysregulation, inflammatory responses, oxidative stress, and metabolic disturbances. Interferon-stimulated gene 15 (ISG15), a ubiquitin-like protein, regulates diverse biological processes—including antiviral immunity, cellular metabolism, oxidative stress, and DNA damage response—through ISGylation, which covalently conjugates ISG15 to target proteins. In recent years, the potential role of ISG15 in pregnancy-related diseases has attracted growing interest. This review systematically outlines the molecular characteristics and functions of ISG15, with a focus on its research advances in preeclampsia, recurrent spontaneous abortion, preterm birth, and fetal growth restriction. Furthermore, it discusses the potential of ISG15 as a novel biomarker or therapeutic target for pregnancy-related disorders, providing new insights for early prevention and clinical management. Collectively, this review positions ISG15 as a critical regulator in pregnancy-related pathologies and underscores its translational potential.</p>