Sepsis-induced skeletal muscle atrophy and weakness is due in part to decreased mTORC1-mediated protein synthesis and increased proteolysis via the autophagy-lysosomal system and ubiquitin-proteasome pathway. The REDD (Regulated in development and DNA damage)-1 protein is increased in sepsis and can negatively regulate mTORC1 activity. However, the contribution of REDD1 to the sepsis-induced change in muscle protein synthesis and degradation has not been determined. Sepsis was produced by cecal ligation and puncture in female REDD1-/- or wildtype (WT) mice and endpoints were assessed 24 h later in gastrocnemius; time-matched, pair-fed controls of each genotype were included. Sepsis increased REDD1 protein 300% in WT mice while REDD1 was absent in REDD1-/- muscle. Sepsis decreased protein synthesis and phosphorylation of downstream targets of mTORC1 (S6K1 T³⁸⁹, rpS6 S^240/244, 4E-BP1 S⁶⁵) in WT but not REDD1-/- mice. However, Akt and PRAS40 phosphorylation was suppressed in both sham and septic muscle from REDD1-/- mice, despite unaltered PDK1, PP2A or TSC2 expression. Sepsis increased autophagy as indicated by decreased ULK1 S⁷⁵⁷ phosphorylation and p62 abundance, and increased LC3B-II/I in WT mice, while these changes were absent in septic REDD1-/- mice. Conversely, REDD1 deletion did not prevent the sepsis-induced decrease in IGF-I mRNA or the concomitant increase in IL-6, TNF-α, MuRF1 and atrogin1 mRNA expression. Lastly, 5 day survival in a separate set of septic mice did not differ between WT and REDD1-/- mice. These data highlight the central role of REDD1 in regulating both protein synthesis and autophagy in skeletal muscle during sepsis.