Ondansetron (ODS) is an effective antiemetic drug which suffers from limited solubility and bioavailability during oral administration due to first-pass metabolism. However, these limitations can be mitigated through inclusion complexation with cyclodextrins (CDs). In this study, we have reported the electrospinning of polymer-free, free-standing ODS/CD nanofibrous webs (NW), a promising approach for developing a fast-disintegrating delivery system of an antiemetic drug molecule. Highly water soluble hydroxypropyl-beta-cyclodextrins (HPβCD) were used as both complexation agent and electrospinning matrix. The computational study revealed that the 1/2 (drug/CD) stoichiometry was more favorable compared to 1/1. The ODS/HPβCD NW was obtained with higher loading efficiency (∼96 %) compared to the control sample of ODS/polyvinyl alcohol (PVA) NW (∼80 %). The amorphous distribution of ODS raised by complexation and the highly water-soluble nature of HPβCD resulted into faster and better release profile and quite faster disintegration property (∼2 s) in artificial saliva than polymeric ODS/PVA NW. Here, ODS/HPβCD NW was generated in the absence of a toxic solvent or chemical to enable the drug loading in an amorphous state. From all reasons above, ODS/HPβCD NW might be a promising alternative to the polymeric based systems for the purpose of fast-disintegrating oral drug delivery.