Objectives: To evaluate the efficacy and safety of domperidone and metoclopramide used by breastfeeding women. Methods: A systematic literature search retrieved citations from PubMed, Embase, The Cochrane Library, Medline, EBSCO, Web of Science, ClinicalTrials.gov (from inception to January, 2021) and bibliographies of known articles. Randomized controlled trials exploring the effects of domperidone and metoclopramide in breastfeeding women with term and preterm infants experiencing adequate or low milk supply were identified. Human milk volume and maternal side effects were presented as mean difference (MD) or relative risks (RR) with 95% confidence intervals (CI). Results: Sixteen trials involving 729 women were included in the qualitative analysis and 14 trials involving 607 women were included in the meta-analysis. In mothers of preterm infants with low milk supply, domperidone demonstrated a significant increase in daily human milk volume (MD = 90.53 mL/day, 95% CI [65.42 to 115.64], I-2 = 9%). However, metoclopramide did not show significant difference in daily human milk volume in women with preterm infants (MD = -1.14 mL/day, 95% CI [-31.42 to 29.14], I-2 = 0%). No differences in maternal side effects were noted with domperidone (RR = 1.20, 95% CI [0.74 to 1.97], I-2 = 0%) or metoclopramide (RR = 1.05, 95% CI [0.52 to 2.11], I-2 = 27%) in women with preterm infants. Regarding the women with term infants, there were insufficient data in the current review. Conclusions: Domperidone can be used to treat low milk supply in women with preterm infants without significant side effects based on the current review. More evidence exploring the efficacy and safety of domperidone and metoclopramide are still needed for breastfeeding women in the future.