Sepsis, a critical medical emergency, continues to pose a substantial worldwide healthcare challenge that necessitates innovative approaches for enhanced treatment. Hence, this study aimed to develop multifunctional biomimetic vancomycin (VCM)-loaded nanoplexes (VCM-FU-PEP-NPs) utilizing a novel antimicrobial peptide (CC-19 peptide) and Fucoidan (FU) to target the Toll-like receptor (TLR) inflammatory pathway and augment the antibacterial efficacy against bacterial sepsis. The CC-19 peptide (CRPRKWIKIKFRCKSLKFC) was designed utilizing computer-aided drug design tools and subsequently synthesized. The biomimetic properties of FU were assessed through in silico and in vitro binding studies, demonstrating a strong affinity for TLR2. The formulated VCM-FU-PEP-NPs demonstrated appropriate physicochemical characteristics, physical stability, and biocompatibility. Moreover, VCM-FU-PEP-NPs exhibited a 2-fold increase in antibacterial efficacy against sensitive Staphylococcus aureus, superior and sustained antibacterial activity against MRSA over 72 h, 5-fold improvement in MRSA biofilm eradication, faster bacterial-killing kinetics, and significantly greater disruption of MRSA membranes, in comparison to bare VCM. Furthermore, VCM-FU-PEP-NPs exhibited excellent DPPH radical scavenging capacity and significant anti-inflammatory efficacy in cells exposed to bacterial toxins. Accordingly, VCM-FU-PEP-NPs demonstrate promise as a potential innovative, multifunctional antibiotic nanocarrier for advancing the treatment of sepsis.