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COVID-19 infection in the pediatric population usually leads to a mild illness; however, a rare but serious complication of MIS-C has been seen in children. MIS-C usually presents 2–4 weeks after COVID-19 infection or exposure, and rare reports have been documented in neonates. Vaccinations for COVID-19 have been approved for children aged 6 months and above in the United States, and recent reports suggest significantly low prevalence and risk of complications of Multi-organ Inflammatory Syndrome (MIS-C) in vaccinated children compared to unvaccinated children. Vaccinations for COVID-19 are safe and recommended during pregnancy and prevent severe maternal morbidity and adverse birth outcomes. Evidence from other vaccine-preventable diseases suggests that through passive transplacental antibody transfer, maternal vaccinations are protective against infections in infants during the first 6 months of life. Various studies have demonstrated that maternal COVID-19 vaccination is associated with the presence of anti-spike protein antibodies in infants, persisting even at 6 months of age. Further, completion of a 2-dose primary mRNA COVID-19 vaccination series during pregnancy is associated with reduced risk for COVID-19–associated hospitalization among infants aged 6 months or less. Therefore, it can be hypothesized that maternal COVID-19 vaccination can reduce the risk of and severity of MIS-C in infants. In this article, we review the literature to support this hypothesis.