The health crisis caused by severe multidrug resistance increasingly compels the exploitation of new alternative antibacterial drugs. A library of structurally unique dihydropyrimidinone imidazoles as novel potential antibacterial agents was developed with the aim to confront drug resistance. Some target compounds exhibited strong antibacterial activities, especially, sulfamethoxazole hybridized dihydropyrimidinone imidazole 8b was found to be extremely active against multidrug-resistant K. pneumonia and A. baumanii at a low concentration of 0.5 μg/mL, which outperformed norfloxacin even clinafloxacin. This active compound not only exhibited low cytotoxicity to mammalian cells (human red blood cells, HepG2 and ECs), but also possessed rapid bactericidal property, good biofilm inhibition ability, and a low propensity to induce K. pneumonia and A. baumanii resistance. Further studies revealed that the inhibitory effect of the active compound 8b might be achieved by disrupting membrane integrity, increasing ROS generation, reducing GSH activity and interacting with DNA. These findings provided a bright hope for developing dihydropyrimidinone imidazoles to combat emergent drug resistance.