Dysmenorrhea is highly prevalent and undertreated, substantially impairing quality of life in reproductive-age individuals. Excessive uterine contractility is widely considered a key mechanistic contributor to menstrual pain. We conducted a systematic search of PubMed and Embase from inception to 24 July 2024 using MeSH and Emtree terms related to dysmenorrhea, uterine contractions and pharmacologic therapy. We included English-language human clinical trials in non-pregnant, reproductive-age participants with primary dysmenorrhea evaluating drugs intended to reduce uterine contractions and menstrual pain, compared with placebo or pre-treatment baseline. Two reviewers independently extracted data using a piloted Cochrane-based form; risk of bias was assessed using RoB 2 and ROBINS-I with disagreements resolved by consensus. Across 25 eligible trials (447 participants), nonsteroidal anti-inflammatory drugs (NSAIDs) most consistently reduced both menstrual pain and uterine contractions. Smaller trials suggested potential benefits for additional pharmacologic classes, including prostaglandin synthesis inhibitors, vasopressin antagonists, beta-adrenergic agonists, combined oral contraceptives, calcium channel blockers, and selective estrogen receptor modulators, whereas oxytocin antagonists showed mixed results. Risk of bias was low in nine studies, moderate in 12, and high in four. These findings support that established therapies for dysmenorrhea (NSAIDs and hormonal contraception) reduce pain and uterine activity, and suggest that other contractility-targeting agents warrant further rigorous evaluation, particularly given meaningful non-response to NSAIDs. PROSPERO registration: CRD42023442828 (registered 24 July 2023).