We have previously reported that Smad6, one of the inhibitory Smads of transforming growth factor‐β (TGF‐β)/bone morphogenetic protein (BMP) signaling, inhibits Toll‐like receptor (TLR) 4 signaling by disrupting the Pellino‐1‐mediated TLR4 signaling complex. Here, we developed Smaducin‐6, a novel membrane‐tethered palmitic acid‐conjugated Smad6‐derived peptide composed of amino acids 422–441 of Smad6. Smaducin‐6 interacted with Pellino‐1, located in the inner membrane, thereby disrupting the formation of IRAK1‐, RIP1‐, IKKε‐mediated TLR4 signaling complexes. Systemic administration of Smaducin‐6 showed a significant therapeutic effect on mouse TLR4‐mediated inflammatory disease models, cecal‐ligation–puncture (CLP)‐induced sepsis, and lipopolysaccharide‐induced endotoxemia, by inhibiting pro‐inflammatory cytokine production and apoptosis while enhancing neutrophil migration and bacterial clearance. Our findings provide clues to develop new peptide‐based drugs to target Pellino‐1 protein in TLR4 signaling pathway for the treatment of sepsis.