Salmonellosis is one of the most common and widely distributed food borne diseases caused by Salmonella enterica serovar Typhi (S.Typhi). Powerful strategies of drug design such as targeting unique effectors of this pathogen are required for combating the emergence of multi drug resistant strains which have become a serious public health problem. The cell invasion protein, SipB has been identified as a potential target which is known to be involved in important functions like host cell entry, transfer of other effector proteins into the host cell, inducing macrophage apoptosis, activating proapoptotic enzyme caspase I for inducing autophagy. This study reports the structure of SipB determined by the combination of homology modelling and comparative modelling techniques. Further 75 natural compounds have been identified as inhibitors and allowed to dock at the binding site, 10 shown to have better dock score and interactions with amino acid residues Glu394, Asn489, Gln517 and Asn562. Further investigations into the antipathogenic potential of caffic acid and phloretin analog compounds may open new avenues for drug development in the control of antibiotic resistant pathogens.