Applying hydrophilic coatings on polymeric nanofibers combined with layered double hydroxide (LDH) not only enhances the efficiency of drug delivery systems but also increases cell adhesion. This work aimed to prepare poly(vinyl alcohol)/sodium alginate (PVA/SA) (2/1)-coated poly(lactic acid) (PLA) nanofibers containing curcumin-loaded layered double hydroxide (LDH) and to investigate their drug release and mechanical properties and their biocompatibility. The optimum PLA nanofibrous sample was considered to be that based on 3 wt% of curcumin-loaded LDH (PLA-3%LDH) with a drug encapsulation efficiency of ∼18% in which a minimum average nanofiber diameter of ∼476 nm along with a high tensile strength of 3.00 MPa were obtained. In the next step, a PVA/SA (2/1) layer was coated on the PLA-3%LDH; as a result, the hydrophilicity of the sample was improved and the elongation at break was decreased remarkably. In this regard the cell viability reached 80% for the coated PLA. Moreover, the formation of a layer of (PVA/SA) on the PLA nanofibers lowered the burst release and resulted in a more sustained drug release, which is a vital feature in dermal applications. A multiscale modeling method was applied for simulation of the mechanical properties of the composite scaffold and the results showed that this method can predict the data with 83% accuracy. The results of this study indicate that the formation of a layer of PVA/SA (2/1) has a significant effect on hydrophilicity and consequently improves cell adhesion and proliferation.