In this paper, the degradation of fluconazole drug (Flz) was explored kinetically utilizing permanganate ion [MnO4 −] as an oxidant in different acidic environments, namely sulfuric and perchloric acids at various temperatures. Stoichiometry of the reactions between Flz and [MnO4 −] in both acidic environments was attained to be 1.2 ± 0.07 mol. The kinetics of the degradation reactions in both cases were the same, being unit order regarding [MnO4 −], fewer than unit orders in [Flz], and fractional second orders in acid concentrations. The rate of oxidative degradation of fluconazole in H2SO4 was higher than that in HClO4 at the same investigational circumstances. The addition of small amounts of Mg2+ and Zn2+ enhanced the degradation rates. The activation quantities were evaluated and debated. The gained oxidation products were characterized using spot tests. A mechanistic approach for the fluconazole degradation was suggested. Finally, the rate law expressions were derived which were agreed with the acquired outcomes. The rates of degradation for various [Flz] were mathematically modeled using the response surface methodology (RSM). The RSM model’s conclusions and the experimental findings are in agreement. The oxidative degradation mechanism of Flz using density functional theory (DFT) was performed. The fluconazole drug degrades in acidic settings, protecting both the environment and human health, according to a method that is easy to use, powerful, inexpensive, practical, affordable, and safe.