Cannabidiol (CBD) has received great scientific interest due to its numerous therapeutic applications. Degradation in the gastrointestinal (GI) tract, first-pass metabolism, and low water solubility restrain bioavailability of CBD to only 6% in current oral administration. Lipid-based nanocarriers are delivery systems that may enhance accessibility and solubility of hydrophobic payloads, such as CBD. Conventional lecithin-derived liposomes, however, have limitations regarding stability in the GI tract and long-term storage. Ether lipid-based archaeosomes may have the potential to overcome these problems due to chemical and structural uniqueness. In this study, we compared lecithin-derived liposomes with archaeosomes in their applicability as an oral delivery system of CBD. We evaluated drug load, storage stability, stability in a simulated GI tract, and in vitro particle uptake in Caco-2 cells. Loading capacity was 6-fold higher in archaeosomes than conventional liposomes while providing a stable formulation over six months after lyophilization. In a simulated GI tract, CBD recovery in archaeosomes was 57 ± 3% compared to only 34 ± 1% in conventional liposomes and particle uptake in Caco-2 cells was enhanced up to 6-fold. Our results demonstrate that archaeosomes present an interesting solution to tackle current issues of oral CBD formulations due to improved stability and endocytosis.