ABSTRACT: The increase of multidrug-resistant pathogens of human and animal origins is a major public health concern. For a better understanding of the health consequences of multidrug-resistant bacteria transmitted from animal products to humans, the host interaction of zoonotic Salmonella isolates along with other pathogenic and commensal bacteria was evaluated using a human intestinal Caco-2 cell system. Multidrug-resistant S. Agona, S. Heidelberg, and S. Typhimurium possessed plasmid-mediated class 1 integrons. The S. Typhimurium DT104 isolate from ground beef showed the well-known genotypic and phenotypic resistance characteristics of the species, and contained the chromosomally located class 1 integron. Among the multidrug-resistant Salmonella isolates, the S. Heidelberg 219 had the highest invasion number at 1.0 × 104 CFU/mL, followed by the S. Typhimurium DT104 isolate at 7.7 × 103 CFU/mL. Listeria monocytogenes was the best performer among the tested species in invading the Caco-2 cell. Multidrug-resistant opportunistic pathogens Klebsiella pneumoniae and Pseudomonas aeruginosa were also able to invade the cells. The invasion of S. Heidelberg 219, S. Typhimurium DT104, L. monocytogenes, K. pneumoniae, and P. aeruginosa into the Caco-2 cells was not affected even in the presence of commensal E. coli. During the intracellular growth of S. Heidelberg 219, S. Typhimurium DT104, and L. monocytogenes, the bacterial counts increased 2 log cycles in 9 h in the Caco-2 cells. Therefore, these strains could rapidly proliferate after their invasion into the cells.