Enterobacteriaceae pathogens such as Escherichia coli, Salmonella sp., Shigella sp., Proteus sp., and Klebsiella pneumoniae cause a wide range of gastrointestinal and other mucosal infections. These bacteria acquire antibiotic resistance very quickly and evolve into multi-drug resistant strains thereby making the treatment very difficult. The outer membrane proteins (OMPs) in Enterobacteriaceae are potential vaccine candidates owing for their high immunogenicity and amino acid conservation. The OmpA is one such protein which need to be investigated for the development of a potential subunit vaccine against multiple infections casued by the pathogens of Enterobacteriaceae. To investigate this, we expressed and purified the highly conserved OmpA of S. typhimurium and studied the antibody mediated cross reactivity with the other Enterobacteriaceae pathogens. This was validated through dot ELISA performed with the hyperimmune sera raised against rOmpA of S. typhimurium. We further analyzed the sequence of OmpA protein and clearly understood that the B-cell epitopes in the protein are highly conserved are responsible for cross reactivity among the Enterobacteriaceae pathogens. This work led to findings that provide strong evidence for the application of OmpA in broad-spectrum subunit vaccine against enteric infections.