Sepsis disrupts skeletal muscle proteostasis and mitigates the anabolic response to leucine (Leu) in muscle of mature animals. We have shown that Leu stimulates muscle protein synthesis (PS) in healthy neonatal piglets. To determine if supplemental Leu can stimulate PS and reduce protein degradation (PD) signaling in neonatal muscle during endotoxemia, overnight fasted neonatal pigs were infused for 8 h with LPS or saline while plasma amino acids, glucose, and insulin were maintained at fasting levels during pancreatic-substrate clamps. Leu or saline was infused during the last hour. Markers of PS and PD were determined in skeletal muscle. Compared to controls, Leu increased PS in longissimus dorsi (LD), gastrocnemius, and soleus muscles. LPS decreased PS in these 3 muscles by 36%, 28%, and 38% but Leu antagonized that reduction by increasing PS by 84%, 81%, and 83%, respectively, when supplemented to LPS. Leu increased eIF3b-raptor interaction, 4EBP1 and S6K1 phosphorylation, and eIF4E·eIF4G complex formation in LD, gastrocnemius, and soleus of control and LPS treated pigs. In LD, LPS increased LC3-II to LC3 ratio and MuRF-1 abundance, but not Atrogin-1 abundance or AMPKα phosphorylation. Leucine supplementation to LPS treated pigs reduced LC3-II/LC3 ratio, MuRF-1 abundance, and AMPKα phosphorylation when compared to LPS alone. In conclusion, parenteral Leu supplementation attenuates the LPS-induced reduction in PS by stimulating mTORC1-dependent translation and may reduce PD by attenuating autophagy-lysosome and MuRF-1 signaling in neonatal skeletal muscle.