Water quality is threatened by numerous pollutants, among which antibiotics are of great concern due to their widespread use and unaltered excretion, leading to water contamination and fostering antibiotic resistance. To comprehensively address sustainable water remediation, herein, the susceptibility to non-thermal plasma degradation of two veterinary antibiotics (Oxytetracycline (OTC) and Lincomycin (LNC)) are compared in an integral approach, including computational analyses, plasma irradiation assays, and a byproduct toxicity assessment. The computational assessment was performed by evaluating the ionization potential (IP) obtained from Density Functional Theory calculations and determining the antibiotics’ susceptible sites for radical attack. Plasma irradiation achieved nearly complete degradation (~100%) of both compounds with the initial concentration of 1 mg L⁻¹, while 60% degradation was observed when the starting concentration was 10 mg L⁻¹. The mineralization rates were 21% and 31% for OTC and LNC, respectively. The degradation profiles followed similar trends, as expected from their comparable IP values. After treatment, the solution exhibited lower biotoxicity compared to the original antibiotics. Therefore, this work represents a step forward in addressing one of the key environmental challenges of our time and encourages further extending the analysis towards the remediation of water polluted with many other organic compounds.