BACKGROUND: The temporal and spatial change in trends of antimicrobial resistance (AMR) in typhoid have not been systematically studied, and such information will be critical for defining intervention, as well as planning sustainable prevention strategies. METHODOLOGY AND FINDINGS: To identify the phenotypic trends in AMR, 13,833 individual S. Typhi isolates, reported from 1973 to 2018 in 62 publications, were analysed to determine the AMR preponderance over time. Separate analyses of molecular resistance determinants present in over 4,000 isolates reported in 61 publications were also conducted. Multi-drug resistant (MDR) typhoid is in decline in Asia in a setting of high fluoroquinolone resistance while it is on the increase in Africa. Mutations in QRDRs in gyrA (S83F, D87N) and parC (S80I) are the most common mechanisms responsible for fluoroquinolone resistance. Cephalosporin resistant S. Typhi, dubbed extensively drug-resistant (XDR) is a real threat and underscores the urgency in deploying the Vi-conjugate vaccines. CONCLUSION: From these observations, it appears that AMR in S. Typhi will continue to emerge leading to treatment failure, changes in antimicrobial policy and further resistance developing in S. Typhi isolates and other Gram-negative bacteria in endemic regions. The deployment of typhoid conjugate vaccines to control the disease in endemic regions may be the best defence.