The growing concerns regarding the immunogenicity of polyethylene glycol (PEG) have prompted the search for alternative excipients that can prolong circulation in parenteral drug delivery. Archaeal lipids, known for their structural stability and unique membrane properties, represent a promising material in this context. In this study, we evaluated the impact of archaeal lipid‐based liposomes on the pharmacokinetics of intravenously administered vancomycin in male Wistar rats. Liposomes containing either purified caldarchaeol (GDGT) or an archaeal lipid extract (ALE), consisting of 5 lipid species, were compared to conventional PEGylated liposomes and free vancomycin regarding their effect on systemic exposure of vancomycin. All liposomal formulations significantly enhanced exposure and yielded a prolonged circulation time compared to the free drug. GDGT containing liposomes achieved pharmacokinetic effects comparable to PEGylated systems, markedly reducing clearance and central volume of distribution based on population pharmacokinetic modeling. Our findings provide the first in vivo evidence that archaeal lipids, particularly GDGT, might act as effective PEG replacement excipient for parenteral delivery, offering a promising alternative platform.