During pregnancy, fetal glucose production is suppressed, with rapid activation immediately post-partum. Fatty acid-binding protein 4 (FABP4) was recently demonstrated as a regulator of hepatic glucose production and systemic metabolism in animal models. Here we studied FABP4’s role in regulating neonatal glucose hemostasis. Serum samples were collected from pregnant women with normoglycemia or gestational diabetes at term, from the umbilical circulation, and from the newborns within 6 hours of life. FABP4 level was higher in the fetal vs. maternal circulation with a further rise in neonates after birth by ~3-fold. Neonatal FABP4 inversely correlated with blood glucose with ~10-fold increase in hypoglycemic neonates. When studied in mice, blood glucose of 12hr-old wild-type, Fabp4 -/+ and Fabp4 -/- littermate mice was 59±13 ng/dL, 50±11 mg/dL and 43±11 mg/dL, respectively (p<0.05). Similar to our observations in humans, FABP4 levels in wild-type mice neonates was ~8-fold higher compared to adult mice. RNA-Seq of neonatal liver suggested altered expression of multiple glucagon-regulated pathways in Fabp4 -/- mice. Indeed, Fabp4 -/- liver glycogen was inappropriately intact, despite a significant hypoglycemia, with rapid restoration of normoglycemia upon injection of recombinant FABP4. Our data suggest an important biological role for the adipokine FABP4 in the orchestrated regulation of post-natal glucose metabolism.