Preterm birth, a leading cause of neonatal morbidity and mortality worldwide, continues to pose a significant clinical challenge, particularly as rates rise in certain populations. Effective prevention strategies hinge on identifying women at risk, often through a history of prior preterm birth or the detection of a mid-trimester short cervix on transvaginal ultrasound. Progesterone, a hormone critical for pregnancy maintenance, has emerged as a cornerstone therapy for reducing preterm birth risk in specific at-risk populations. Its mechanism of action includes promoting uterine quiescence by modulating inflammatory pathways, delaying cervical ripening, and inhibiting myometrial contractions, thereby extending gestational age. Vaginal progesterone has demonstrated efficacy in singleton pregnancies with a mid-trimester short cervix (≤25 mm), where it reduces preterm birth rates and improves neonatal outcomes. These findings form the basis for current guideline recommendations supporting its use in this population. However, the role of progesterone in women with a previous preterm delivery remains more contentious, and recent guidelines advise against its routine use. While some studies suggest potential benefits in twin pregnancies with a short cervix, other trials have yielded inconsistent results, and further evidence is needed. For pregnancies beyond 24 weeks or following arrested preterm labor, progesterone’s effectiveness is not well-established, with available studies demonstrating conflicting results. As preterm birth remains a multifaceted challenge, additional high-quality research is needed to refine the indications, dosing, and timing of progesterone therapy, especially in multiple gestations and other high-risk groups.