Toll-like receptor 4 (TLR4) activation during infection or inflammatory insult can induce pro-inflammatory cytokines that adversely impact fetal development and growth, and increase susceptibility to metabolic diseases in later life. We utilized a mouse model to investigate the utility of a small molecule TLR4 antagonist (+)-naloxone, the non-opioid isomer of the opioid receptor antagonist (-)-naloxone, in protecting the offspring from altered fetal programming induced by a modest systemic inflammatory challenge. Pregnant C57B/6 females (n=8/group) were administered low dose (20 μg/kg) intraperitoneal lipopolysaccharide (LPS) on gestation day (GD)16.5, with or without (+)-naloxone and the females were killed 4 hours later to collect fetal brain, fetal membrane, placenta, decidua and uterus tissues (2 fetal sites/female) for qPCR analysis of inflammatory cytokines. In adult progeny exposed to LPS challenge in utero, male but not female offspring exhibited elevated adipose tissue, reduced muscle mass and elevated plasma leptin at 20 weeks of age. (+)-naloxone attenuated the effects of in utero LPS exposure on offspring allometry and leptin. (+)-naloxone treatment alone elicited accelerated post-weaning growth and elevated muscle, fat and bone mass in adult male offspring, and elevated bone mass in females. qPCR showed that LPS induce expression of inflammatory cytokines Il1a, Il1b, Il6, Tnf and Il10 in fetal, placental and uterine tissues of pregnant mice, and treatment with (+)-naloxone was found to suppress induction of the inflammatory cytokines caused by LPS. Fetal sex-specific effects were observed, with higher expression levels of Il1A, Il1B, Il6 and Il10 induced by LPS in implantation sites of male fetuses. Greater suppression of Il6 levels was observed in implantation sites of female fetuses following co-treatment with (+)-naloxone. These data demonstrate that suppression of TLR4 signaling with (+)-naloxone provides protection from inflammatory injury in utero, to attenuate long-term developmental effects of excessive TLR4 activation, in a fetal sex-specific manner.