In this study, we present a potential alternate approach for the treatment of melanoma skin cancer and skin tissue regeneration, a comparison of polycaprolactone (PCL) and polycaprolactone blended with linear (LPEI) and branched polyethylenimine (BPEI). This research presents the biocompatibility and feasibility of PCL, PCL loaded with LPEI and PCL loaded with BPEI in different concentrations, producing electrospun scaffolds. SEM images show that the nanofibers developed between 74 ± 419 nm. Contact angle assay demonstrated high hydrophobicity for all mats, which could be overcome by surface modification, namely, plasma treatment, ameliorating the hydrophilicity of the mats, providing excellent cells adhesion to the scaffolds surface. We demonstrate the biocompatibility of the scaffolds developed by electrospinning techniques, followed by in vitro tests with Human Dermal Fibroblasts (HDFs) and murine melanoma cells (B16), by using MTT assay to determinate the biocompatibility with all cells, and confocal images to give as insights of cell morphology (nucleus and cellular membrane). Sirius red collagen assay was performed for HDFs to give the collagen release profile after 6 days of incubation, and the possibility of the mats to help in skin regeneration process by forming extra cellular matrix (ECM). The CFMDA dye suggested no cytotoxicity for HDFs to monitor the morphology of live cells. The results have shown that all the scaffolds developed have good cell adhesion and proliferation properties. We could also observe high cytotoxicity for B16 melanoma cells for PCL_BPEI nanofibers. This primary in vitro study suggests that the mats developed may increase the skin regeneration process and at the same time promote apoptosis of melanoma cells, therefore it can be an emerging technology for skin regeneration, wound healing process and treatment of melanoma through electrospun drugs delivery system.