Herein, hydroxypropyl-beta-cyclodextrin (HPCD) inclusion complex (IC) of a hydrophobic drug, sul- fisoxazole (SFS) was incorporated in hydroxypropyl cellulose (HPC) nanofibers (HPC/SFS/HPCD-IC-NF) via electrospinning. SFS/HPCD-IC was characterized by DSC to investigate the formation of inclusion complex and the stoichiometry of the complex was determined by Job’s plot. Modeling studies were also performed on SFS/HPCD-IC using ab initio technique. SEM images depicted the defect free uniform fibers and confirmed the incorporation of SFS/HPCD-IC in nanofibers did not alter the fiber morphology. XRD analyses showed amorphous distribution of SFS/HPCD-IC in the fiber mat. Release studies were performed in phosphate buffered saline (PBS). The results suggest higher amount of SFS released from HPC/SFS/HPCD-IC-NF when compared to free SFS containing HPC nanofibers (HPC/SFS-NF). This was attributed to the increased solubility of SFS by inclusion complexation. Sandwich configurations were prepared by placing HPC/SFS/HPCD-IC-NF between electrospun PCL nanofibrous mat (PCL-HPC/SFS/HPCD-IC-NF). Consequently, PCL-HPC/SFS/HPCD-IC-NF exhibited slower release of SFS as compared with HPC/SFS/HPCD-IC-NF. This study may provide more efficient future strategies for developing delivery systems of hydrophobic drugs.