Background: Piroxicam exhibits low oral bioavailability due to its meagre solubility in water. The intent of the study described below was to ameliorate bioavailability of the drug by employing a solubility-enhancing encapsulation technique.Methods: Seven samples were formulated with piroxicam and gelatin using both the solvent evaporation method and electrospraying method together. Evaluation of solubility and release rate in water, and assessment of bioavailability in rats were carried out in comparison with piroxicam plain drug powder (PPDP). Other in vitro explorations were accomplished using powder X-ray diffraction (PXRD) analysis, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy.Results: All the piroxicam-loaded gelatin-nanocontainers (PLGNs) enhanced solubility and release of the payload in water. In particular, a PLGN formulation consisting of piroxicam and gelatin at 1/8 (w/w) ratio presented about 600-times greater solubility of the drug than that shown by PPDP. Moreover, 85.12 ± 10.96% payload was released from this formulation in 10 min which was significantly higher than that dissolved from PPDP in 10 min (11.81 ± 5.34%). The drug content, drug loading and encapsulation efficiency of this formulation were 93.41± 0.56%, 10.45± 0.06% and 66.74± 6.87%, respectively. The drug loaded in PLGNs existed in the amorphous state as confirmed by XRD and DSC analyses, and it was more stable when analyzed by TGA. Moreover, FTIR spectroscopic analysis suggested non-existence of any piroxicam-gelatin interaction in the formulation. In the SEM image, PLGNs appeared as round-shaped and smooth-surfaced particles, exhibiting a particle size of <1000 nm. Amelioration in bioavailability of piroxicam with the above-mentioned PLGN formulation was 4-fold as compared to that with PPDP.Conclusion: The PLGN formulation fabricated with piroxicam and gelatin at 1/8 (w/w) might be a promising system for enhanced biopharmaceutical performance of the drug.