Enterobacter aerogenes is a common cause of hospital-acquired infections such as pneumonia and urinary tract infections. Multidrug-resistant strains have emerged as a public health threat. In this study, we used a non-expensive method called the sponge-like reduced protocol (SLRP) to create E. aerogenes bacterial ghosts EAGs (deactivated bacteria) and evaluated their safety and immunogenicity in mice. The mice were given three doses of EAGs or EAGs with an adjuvant and then challenged with live E. aerogenes bacteria. The results showed that the EAG-immunized mice had higher levels of specific antibodies IgG, IgA, and IgM, lower bacterial load in internal organs after challenge, and improved histopathological examination of the liver and spleen compared to a negative control group. The serum from the EAG-immunized mice also had cross-reactivity with other Enterobacteriaceae pathogens using western blotting and enzyme-linked immunosorbent assay (ELISA). These findings suggest that the EAG vaccine may be an effective and safe alternative for the prevention and control of multidrug-resistant infections caused by E. aerogenes. This study showed that E. aerogenes ghosts could potentially be used as a vaccine.