This study evaluated the synergistic antibacterial and antibiofilm effects of combining meropenem with zinc oxide nanoparticles (ZnO-NPs) against multidrug-resistant Pseudomonas aeruginosa and investigated its therapeutic potential in bacterial keratitis. All tested clinical isolates were resistant to meropenem; however, combining meropenem with ZnO-NPs produced strong antimicrobial synergy. The MIC of meropenem decreased from 512 to 4 µg/mL, while the MIC of ZnO-NPs decreased from 64 to 8 µg/mL, yielding a Fractional Inhibitory Concentration Index (FICI) of 0.132, indicating significant synergism. ZnO-NPs reduced biofilm biomass by 70–85%, and SEM analysis demonstrated almost complete eradication of biofilms following combination treatment. Furthermore, expression of the biofilm-associated genes lasR, pslA, and fliC was reduced by approximately 2–4 fold after treatment. In a rat model of P. aeruginosa-induced bacterial keratitis, the combined therapy significantly reduced corneal opacity and improved clinical outcomes compared with meropenem alone. These findings suggest that combining meropenem with ZnO-NPs represents a promising strategy to overcome antimicrobial resistance and biofilm-associated infections.