A comparative study between archaeosomes, lipid lamellar vesicles made from archaea polar lipids, and conventional phospholipids liposomes was carried out, aiming at evaluating the properties and the potential of archaeosomes as novel colloidal carriers for effective drug delivery to the skin. Betamethasone dipropionate (BMD)-loaded archaeosomes and conventional liposomes were prepared by the thin-lipid film and sonication procedures, using, respectively, archaeal lipids extracted from archaea Halobacterium salinarum and enriched soy phosphatidylcholine. Vesicular formulations were characterized by assessing vesicle size, zeta potential, incorporation efficiency, and morphology. In order to investigate the effect of the incorporation in the two different colloidal carrier systems on the (trans)dermal delivery of BMD, in vitro drug permeation studies through full-thickness pig skin were carried out by using Franz diffusion vertical cells by testing both archaeal and liposomal dispersions. Interestingly, archaeosomes appeared to be the most effective carriers for the model drug, achieveing a major drug penetration and accumulation in the skin strata, especially in the epidermis. This can, presumably, be due to the enhanced archaeosomal bilayer fluidity, as indicated by the rheological studies that provided insight into the viscoelastic properties of all the studied systems. The available data suggest that suitably developed archaeosomes may hold great promise as delivery vehicles for topical applications.