Isooctyl p-methoxycinnamate(OMC) is a commonly used chemical ultraviolet B sunscreen that suffers rapid degradation with current delivery systems following sun exposure. In this study, deoxycholate-mediated liposome (DOC-LS) endocytosis was employed to improve the antioxidation effects of OMC following topical administration, and the in vitro cell uptake was investigated to understand the enhanced cutaneous absorption of the drug via this nanocarrier. Following topical application, structural changes in the stratum corneum were identified. With the increase of DOC content, the drug deposition in skin decreased; from this, a DOC-LS formulation was selected that showed significantly more drug delivery in skin than did the other preparations (P < 0.05). DOC-LS decreased skin resistance, suggesting its ability to induce skin barrier disruption. In vitro HaCaT keratinocyte cell uptake of coumarin-6 incorporated in the two types of phosphatidylcholine (PC) vesicles (i.e., LS or DOC-LS) yielded similar fluorescence intensities following incubation for different periods (P < 0.05). However, CCC-ESF-1 embryonic fibroblast cell uptake of the fluorescence revealed time-dependence, and the emitted light from DOC-LS incubated cells was stronger than that from cells incubated with LS (P < 0.05). These findings might be associated with the endocytic pathway of HaCaT, which mainly exhibited adsorption or physical adhesion of the fluorescent vesicles, whereas CCC-ESF-1 markedly internalized the PC vesicles via the lysosomes, as shown by intracellular fluorescence co-location studies. Following loading with the same amount of OMC, the DOC-LS vesicles exhibited superior skin tissue antioxidative capacity among the preparations tested, corroborating the in vivo skin drug deposition results. Thus, our results suggest that DOC-LS is a promising system for OMC dermal delivery without promoting skin irritation, which is quite advantageous for therapeutic purposes.