The nonsteroidal anti-inflammatory drug Piroxicam is of interest not only in pharmacology and therapeutics but also in structural dynamics. This drug in solution presents several equilibria that depend on its conformational structure and the medium. Piroxicam was studied by total fluorescence by using a chemometric method (parallel factor analysis or PARAFAC) to resolve its spectra. The addition of cyclodextrins can promote the encapsulation of some preferred Piroxicam species and more easily affect the spectral de-convolution. Because each species has a distinct spectrum as a function of the degree of encapsulation, a factorial fractional design (face-centered fractional cubic with a central sample) was considered for different cyclodextrins solutions. It was possible to identify a correlation between some spectra and the isomers and to reach some understanding of the spectroscopic behavior of the drug in cyclodextrin-containing hydrophilic solvents.