In the pursuit of novel therapeutic agents with enhanced antimicrobial properties, a new series of hybrid compounds combining the tetrahydroindolones and dihydropyrimidinones scaffolds is designed and synthesized in good yields. The hybridization strategy aims to merge the distinct biological functionalities of each pharmacophore, leading to synergistic effects. The resulting compounds exhibit significant antibiofilm activity against resistant bacterial Staphylococcus aureus and Pseudomonas aeruginosa strains, indicating that the hybrid framework plays a crucial role in this enhanced performance. To assess the safety profile of the new molecules, toxicity studies are conducted using the Caenorhabditis elegans model. The study reveals no observable toxicity, even at elevated concentrations, suggesting a favorable therapeutic window. The combination of strong antibiofilm activity with nontoxic behavior underlines the antivirulence potential of these compounds, positioning them as promising adjuvants to conventional antibiotics in the fight against chronic bacterial infections.