Nanofibers (NFs) have proven to be very attractive tool as drug delivery plateform among the different plethora of nanosystems, owing to their unique features. They exhibit two- and three-dimensional structures some of which mimic structural environment of the body tissues, in addition to being safe, efficacious, and biocompatible drug delivery platform. Thus, this study embarked on fabricating polyvinyl alcohol/chitosan (PVA/CS) electrospun NFs encapsulating zopiclone (ZP) drug for intranasal brain targeted drug delivery. Electrospun NFs were optimized by adopting a three factor-two level full factorial design. The independent variables were: PVA/CS ratio (X), flow rate (X), and applied voltage (X). The measured responses were: fiber diameter (Y,nm), pore size (Y,nm) and ultimate tensile strength (UTS,Y,MPa). The selected optimum formula had resulted in NFs diameter of 215.90 ± 15.46 nm, pore size 7.12 ± 0.27 nm, and tensile strength around 6.64 ± 0.95 MPa. In-vitro biodegradability testing confirmed proper degradation of the NFs within 8 h. Moreover, swellability and breathability assessment revealed good hydrophilicity and permeability of the prepared NFs. Ex-vivo permeability study declared boosted ex-vivo permeation with an enhancement factor of 2.73 compared to ZP suspension. In addition, optimized NFs formula significantly reduced sleep latency and prolonged sleep duration in rats compared to IV ZP drug solution. These findings demonstrate the feasibility of employing the designed NFs as an effective safe platform for intranasal delivery of ZP for insomnia management.