In combating the global epidemic of multidrug-resistant (MDR-KP), combination therapy with the active ingredient of meropenem (MER) is gaining attention as a new therapeutic approach. In this study, the effect of OAY (orthogonal combination drug of active ingredients in YHPG) in combination with MER on MDR-KP was assessed using the microdilution technique. Additionally, the antimicrobial effect of OAY in combination with MER on MDR-KP was analyzed by reactive oxygen species (ROS), alkaline phosphatase (AKP), and RT-qPCR techniques. Furthermore, the expression levels of critical targets within the NF-κB/NLRP3 pathway were assessed via HE staining and western blot in an MDR-KP-infected mice model. Our results confirmed that the OAY-MER combinations inhibited MDR-KP biofilm formation. In the meantime, the compromise of membrane integrity led to the generation of ROS, which subsequently resulted in a decrease in the activity of intracellular enzymes, specifically AKP. We also found that the combination of OAY-MER reversed tmexCD1-toprJ-mediated MER resistance in MDR-KP. Finally, by a mouse model of MDR-KP infection, the data demonstrated that OAY and YHPG ameliorated lung injury and bacterial infections in the lungs, and significantly reduced NF-κB P-p65, NLRP3, and C-GSDMD protein expression in mouse lung tissues. The findings suggest that the combination of OAY with meropenem may have great potential for clinical application and could provide a theoretical basis for its use in treating MDR-KP infections.