Objectives: In this study, we aimed to incorporate levocetirizine dihydrochloride (LVC) into electrospun nanovesicle-in-nanofiber (NF) scaffolds for combined management of atopic dermatitis and methicillin-resistant Staphylococcus Aureus skin infection, to sustain LVC release for continuous skin improvement. Methods: Firstly, LVC was encapsulated in cerosomes (CERs) by employing a thin-film hydration approach using a 2¹.3¹ factorial design. CERs were assessed by calculating entrapment efficiency (EE%), particle size (PS) and polydispersity index (PDI). In addition, the optimized CERs were further subjected to stability evaluation. After that, the optimized CERs were incorporated into polyurethane nanofibers (NFs) using a coaxial electrospinning technique. An in vitro release assay was used to calculate the amount of LVC released from the LVC-NFs and the optimized CERs-NFs. For morphological assessment of NFs, LVC-NFs and CERs-NFs were subjected to transmission electron microscopy, scanning electron microscopy, and confocal laser scanning microscopy. Atomic force microscopy was utilized to evaluate the roughness of CERs and both NFs. The optimum formulation was further subjected to in vivo study. Results: The optimum CERs exhibited an EE% of 65.03 ± 1.07%, a PS of 680.00 ± 39.50 nm, and a PDI of 0.51 ± 0.04. LVC was released in a sustained manner from CERs NFs. Further, a dermatokinetic study confirmed that CERs-NFs sustained the infiltration of LVC, compared with the other groups. Finally, a safety assessment showed that all formulations were safe when topically applied to rat skin. Conclusions: In conclusion, AD and MRSA skin infections may be cured by employing electrospun nanofiber-scaffold-loaded LVC CERs, which can thus be regarded as a promising system.