In this study, a wound dressing composed of nanofibers was fabricated, mimicking the properties of the extracellular matrix. First, collagen, a biopolymer and wound healing accelerator, was extracted from jellyfish (Catostylus mosaicus). The enzymatic extraction using pepsin yielded 14.58% ± 0.19%, representing a 9.98-fold increase compared to the acidic extraction method. The characterization revealed that the extracted collagen is of type I, with amide bands in its structure, and a denaturation temperature of 28.6 °C. In the second step, the collagenic (C) nanofibers were fabricated from polycaprolactone (PCL) polymer, with the addition of phenytoin (P) to enhance wound healing. The ratio of PCL to collagen and the electrospinning parameters were optimized by response surface design to get optimal nanofibers (PCL-C-P ONFs) that facilitate sustained drug release over two days. The results showed that the predicted drug release from PCL-C-P ONFs exhibited a relative inaccuracy of 1.4% compared to the experimental results after four days. Besides, incorporating collagen and phenytoin into the structure of the nanofibers increased their swelling properties, porosity, and hydrophilicity while decreasing their density. FTIR and XRD analyses confirmed the successful loading of the collagen and drug into the PCL-C-P ONFs. Furthermore, FESEM and thermogravimetric analysis illustrate a bead-free network with an average fiber diameter of 95 nm and an initial decomposition temperature of 280 °C, respectively. In the third step, chitosan (Chi) was added to the fiber structure as a shell layer (PCL-C-P Chi-CSNFs) and blending agent (PCL-C-P-Chi NFs) to enhance the controlled phenytoin release. TEM and FESEM experiments illustrated that the core-shell structure of the nanofibers was formed successfully with a shell thickness and a core diameter of 39 ± 16 nm and 92 ± 21 nm, respectively. The experiments revealed that the presence of a chitosan shell layer increased the porosity