The increasing problem of antimicrobial resistance (AMR), specifically focusing on P. aeruginosa, underscores the need for new anti-pseudomonal compounds. This study uses cutting-edge computer-based strategies for the evaluation of the inhibitory activity of natural compounds Thymol, Curcumin, and Piperine (model polyphenols and alkaloids) on the DNA gyrase of bacteria, which is a well-proven target for antimicrobials, against a quinolone compound. Molecular docking studies were carried out using InstaDock v1.1.exe, calculating binding energies (ΔG), along with the study of biological pharmaceutical properties through the SWISS Drug Design platform (https://www.swissdrugdesign.org/), and toxicity studies using the GUSAR software portal (http://www.pharmaexpert.ru/gusar/). Docking studies reveal the order of compound interaction: Thymol > Curcumin > Quinolone > Piperine, where Thymol was the strongest binder at the ATP pocket of the target protein. However, the results of the analysis of the absorption, Distribution, Metabolization, and Excretion (ADME) of the compounds show that Curcumin is the compound with the highest Safety (LD50) but also exhibits several severe metabolic toxicity (3/5 CYP450 inhibition), also exhibited by Piperine. However, Thymol demonstrates the best metabolic profile, characterized by the absence of CYP inhibitions, high gastrointestinal absorption, and ease of diffusion through the blood-brain barrier. Overall, these studies clearly envisage Thymol for the prospective study for the first time, together with the requirement for specific modifications of Curcumin for overcoming the metabolic toxicity exhibited by the compound.