Electrospun gelatin nanofibrous matrix encapsulating ciprofloxacin (CIP)/hydroxypropyl-beta-cyclodextrin (HPβCD)-inclusion complex (IC) was produced via electrospinning method. Computational modeling indicated that van der Waals forces are the most significant driving forces for the complexation and hydrophobic moiety (piperazinyl) of CIP, which was included in the cavity of HPβCD. The FTIR and XRD studies indicated the formation of CIP/HPβCD host/guest complexation, FTIR also suggested that hydrophobic moiety of CIP is in the HPβCD cavity in parallel with the computational modeling results. The phase solubility diagram demonstrated that the solubility of CIP was enhanced after complexation with HPβCD. SEM images showed that electrospun gelatin nanofibers encapsulating CIP/HPβCD-IC have bead-free morphology with a diameter of ˜90 nm. The gelatin nanofibrous mat loaded with CIP/HPβCD-IC has exhibited fast-dissolving character in water compared to gelatin/CIP nanofibrous mat due to the enhanced wettability of the nanofibrous mat by HPβCD and improvement achieved in the solubility of CIP.