Antibacterial resistance bears a major threat to human health worldwide, causing about 1.2 million deaths per year. It is noteworthy that carbazole derivatives have shown a potential antibacterial activity, for example, 9-methoxyellipticine, which was isolated fromOchrosia ellipticaLabill. roots (Apocynaceae) in the present study. An in vitro screening of the antibacterial activity of 9-methoxyellipticine was investigated against four multidrug-resistant (MDR)Klebsiella pneumoniaeand Shiga toxin-producingEscherichia coli(STEC O157) as Gram-negative bacteria, in addition to Methicillin-resistantStaphylococcus aureus(MRSA) withBacillus cereusas Gram-positive bacteria. The compound had significant antibacterial activity against the two Gram-negative isolates and lower activity against the Gram-positive ones. The synergistic use of 9-methoxyellipticine and antibiotics was successfully effective in reducing the MDR microorganisms. Lung pneumonia and kidney infection mice models were used to investigate the compound’s efficacy in vivo for the first time. Noteworthy reductions inK. pneumoniaeand STEC shedding and the colonization were observed, with a reduction in pro-inflammatory factors and immunoglobulin levels. Other related lesions such as inflammatory cell infiltration, alveolar interstitial congestion, and edema were noticed to occur, lessened to different limits. The anti-STEC and anti-K. pneumoniaeactivities of 9-methoxyellipticine were revealed, providing a new alternative against MDR nosocomial infections.