Background :Typhoid fever remains a public health concern in Harare City, Zimbabwe. Recurrent outbreaks are driven by inadequate water, sanitation, and hygiene infrastructure. In 2019, the typhoid conjugate vaccine (TCV) was introduced. The TCV impact on typhoid epidemiology, antimicrobial resistance (AMR), Salmonella Typhi population, and effectiveness across districts and age groups remains understudied. Methods:Data from 3401 typhoid cases during 2017–2024 were analyzed. Attack rates, risk ratios, AMR, and vaccine effectiveness across prevaccine (2017–2019) and postvaccine (2020–2024) periods were compared. Analysis was stratified by district, vaccination coverage, and age groups. Genomic characteristics of Salmonella Typhi strains isolated postvaccination were investigated and compared to prevaccine populations. Results:Attack rates for the Western district, which reported 70.8% of cases, decreased from 1373/100 000 before TCV to 341/100 000 after (risk ratio: 0.40, P ≤ .0001). Subdistricts had attack rates of 1783 (Glen View), 1687 (Mufakose), and 1145 (Budiriro) per 100 000 before vaccination and 223, 33, and 364/100 000, respectively, after (risk ratio: 0.22, 0.03, 0.48, respectively, P < .0001). The 0–15 age group showed vaccine effectiveness of 81.2% (95% confidence interval, 71.2–88.8), compared to 61.4% (95% confidence interval, 54.3–68.1) across all ages. Genomic comparison of Salmonella Typhi isolates pre- and postvaccination did not indicate changes in bacterial population. AMR phenotypic data and genomic prediction indicated lower resistance to antibiotics postvaccination. Conclusions:TCV reduced typhoid incidence, particularly in high-burden areas and children. No shift in the Salmonella Typhi population was observed. Ongoing transmission underscores need for integrated measures, including human-resource capacity, improved water, sanitation, and hygiene infrastructure, research on vaccine performance variability, and refined multisectoral interventions.