Listeriosis is a severe zoonotic disease caused by Listeria monocytogenes (L. monocytogenes), which can be acquired through animal source foods. This pathogen shows unique virulence fitness allowing it to penetrate and survive inside host cells causing extremely dangerous symptoms. Therefore, we aimed to correlate the clinical outcomes with the antimicrobial resistance and virulence profiles of L. monocytogenes. This is crucial for improving disease management, developing new therapeutic strategies, enhancing public health and food safety, and advancing scientific knowledge. Therefore, we assessed the antimicrobial resistance and virulence profiles of L. monocytogenes isolated from various sources, along with their potential to cause disease, using an in vivo rabbit model. Based on identification criteria, 47 L. monocytogenes isolates (15.7%) were recovered with the highest detection rates among rabbits (22%). Unfortunately, all the investigated isolates showed multidrug resistance (MDR) as well as multi-virulent profiles with 45 highly heterogeneous clusters. Noteworthy, the degree of illnesses of the experimentally infected rabbits was dependent on the virulence profiles. Specific nervous manifestations and severe histopathological alterations were observed in experimental rabbits infected with highly virulent isolates confirming that the potential ability of this pathogen to produce a disease is not always decipherable from its virulence arrays. Finally, it was confirmed that managing infections caused by L. monocytogenes has become increasingly challenging due to its high antimicrobial resistance, strong virulence, and the severe pathological effects linked to its virulence factors.