Homeless infants are known to have poor birth outcomes, but the longitudinal impact of homelessness on health, health care use, and health spending during the early years of life has received little attention. Linking Massachusetts emergency shelter enrollment records for the period 2008-15 with Medicaid claims, we compared 5,762 infants who experienced a homeless episode with a group of 5,553 infants matched on sex, race/ethnicity, location, and birth month. Infants born during a period of unstable housing resulting in homelessness had higher rates of low birthweight, respiratory problems, fever, and other common conditions; longer neonatal intensive care unit stays; more emergency department visits; and higher annual spending. Differences in most health conditions persisted for two to three years. Asthma diagnoses, emergency department visits, and spending were significantly higher through age six. While screening and access to health care can be improved for homeless infants, long-term solutions require a broader focus on housing and income.