For the determination of fluconazole (FLU) oxidation stability under permanganate treatment at the acidic pH, a sensitive, reproducible, and stability-indicating ultra-performance liquid chromatographyñmass spectrometry (UPLC/MS) method was developed. Three additional products (t R = 5.79, 6.98, 7.54) were observed besides the FLU (t R = 6.22). The proposed method was used to study the kinetics of FLU oxidative degradation. An oxidation process followed the kinetics of the second-order reaction. The degradation rate constant and the corresponding half-life obtained for the FLU oxidative degradation were 0.5626 h-1 and 16.69 h, respectively. The putative oxidation products were characterized and their fragmentation pathways, on a basis of MS/MS data, were proposed.