In Mississippi, USA, infant hospitalization with congenital syphilis (CS) spiked by 1,000%, from 10 in 2016 to 110 in 2022. To determine the causes of this alarming development, we analyzed Mississippi hospital discharge data to evaluate trends, demographics, outcomes, and risk factors for infants diagnosed with CS hospitalized during 2016–2022. Of the 367 infants hospitalized with a CS diagnosis, 97.6% were newborn, 92.6% were covered by Medicaid, 71.1% were African American, and 58.0% were nonurban residents. Newborns with CS had higher odds of being affected by maternal illicit drug use, being born prematurely (<37 weeks), and having very low birthweight (<1,500 g) than those without CS. Mean length of hospital stay (14.5 days vs. 3.8 days) and mean charges ($56,802 vs. $13,945) were also higher for infants with CS than for those without. To address escalation of CS, Mississippi should invest in comprehensive prenatal care and early treatment of vulnerable populations.