Peripheral nerve injury is one of the most debilitating pathologies that severely impair patients' life. Although many efforts have been made to advance in the treatment of such a complex disorder, successful strategies to ensure full recovery are still scarce. The aim of the present work was to develop flexible and mechanically resistant platforms intended to act as a support and guide for neural cells during the regeneration process of peripheral nerve injury. For this purpose, poly(lactic-co-glycolic acid) (PLGA)/poly(d,l-lactic acid) (PDLLA)/poly(ethylene glycol) 400 (PEG)-multichannel-based scaffolds (MCs) were prepared through a multistep process involving electrospun microfibers coated with a polymer blend solution and used as a sacrificial mold. In particular, scaffolds characterized by random (MCR) and aligned (MCA) multichannel were obtained. A design of experiments approach (DoE) was employed to identify a scaffold-optimized composition. MCs were characterized for morphological and mechanical properties, suturability, degradability, cell colonization, and in vivo safety. A new biodegradable, biocompatible, and safe microscale multichannel scaffold was developed as the result of an easy multistep procedure.