Background: The emergence of multidrug-resistant (MDR) “Salmonella typhi” is a growing concern globally, with significant implications for public health, especially in endemic regions like Eastern India. A comprehensive understanding of the evolving antimicrobial susceptibility patterns and molecular characteristics of these strains is essential for effective treatment and management. Objective: This review aims to analyze the current trends in antimicrobial susceptibility patterns of “Salmonella typhi” strains emerging in Eastern India and to evaluate the molecular mechanisms underlying resistance based on recent studies. Methods: A systematic review of studies published between 2010 and 2023 was conducted, focusing on the antimicrobial susceptibility patterns and molecular profiles of “Salmonella typhi” isolates from Eastern India. Data were extracted on resistance rates to commonly used antibiotics and on the detection of resistance genes and mutations. Results: The review indicates a marked increase in resistance to first-line antibiotics such as ampicillin, chloramphenicol, and trimethoprim sulfamethoxazole. Resistance to third-generation cephalosporins and fluoroquinolones is also rising, with a significant proportion of isolates harboring extended-spectrum beta-lactamase (ESBL) genes like *bla*CTX M-15 and mutations in quinolone resistance-determining regions (QRDRs). Molecular studies reveal that resistance mechanisms are predominantly mediated by plasmid-encoded genes and chromosomal mutations, with the dissemination of mobile genetic elements contributing to the spread of MDR strains. Conclusion: The review underscores a disturbing trend of increasing multidrug resistance in “Salmonella typhi” in Eastern India, highlighting the critical need for continued surveillance, molecular characterization, and the development of new therapeutic strategies. The findings call for enhanced infection control measures and antibiotic stewardship programs to address the challenges posed by these resistant strains.