Salmonella Typhi (S. Typhi), the invasive typhoidal serovar of Salmonella enterica that causes typhoid fever in humans, is a severe threat to global health. It is one of the major causes of high morbidity and mortality in developing countries. According to recent WHO estimates, approximately 11-21 million typhoid fever illnesses occur annually worldwide, accounting for 0.12-0.16 million deaths. Salmonella infection can spread to healthy individuals by the consumption of contaminated food and water. Typhoid fever in humans sometimes is accompanied by several other critical extraintestinal complications related to the central nervous system, cardiovascular system, pulmonary system, and hepatobiliary system. Salmonella Pathogenicity Island-1 and Salmonella Pathogenicity Island-2 are the two genomic segments containing genes encoding virulent factors that regulate its invasion and systemic pathogenesis. This Review aims to shed light on a comparative analysis of the virulence and pathogenesis of the typhoidal and nontyphoidal serovars of S. enterica.