Degradation kinetics and pathways of the antibiotic penicillin G (Pen) have been examined via oxidation by chromium trioxide (CrVI) in aqueous sulfuric and perchloric acid media. The oxidation reactions were monitored by spectrophotometry at 298 K. In both acidic media, penicillin G oxidation was set to proceed through acid catalysis. The stoichiometry of the reactions designated that 3 moles of Pen required 2 moles of CrVI. The kinetics of Pen oxidation in both acids was of the first order with regard to [CrVI] and less-than unity order with regard to [Pen] and [H+ ] in their variation. The rates of reactions displayed negligible impacts upon altering ionic strengths or dielectric constants of the reaction media. There was no intrusion of free radicals throughout the redox reactions. Addition of low concentrations of Ni2+, Cu2+, and Zn2+ ions enhanced the oxidation rates, while addition of Cr3+ as a described product did not noteworthily alter the rates. Under comparable investigational circumstances, the oxidation rates in HClO4 were almost 2-fold greater than in H2SO4. The oxidation products of penicillin G were identified by spectral analysis and spot tests as phenyl acetic acid, 2-formyl-5,5-dimethyl-thiazolidine-4-carboxlate ion, ammonium ion, and carbon dioxide. Reliance of reaction rates on temperature has been explored, and the activation and thermodynamic parameters were estimated and debated. In view of the noted reactions’ orders and products’ identification, a plausible mechanism for the oxidation reactions was suggested. The derived rate law was set to be in accordance with the acquired results. This study offers an unprecedented simple and low-cost treatment method for removal or degradation of certain pollutants for protecting the environment and human health.