Introduction: Cholera is recurrent in Zambia particularly in Lusaka district where outbreaks occur with regularity, typically during the rainy season. Despite the progress in improving Water, Sanitation, and hygiene (WASH) interventions, outbreaks are still persistent. This research aimed at assessing the effectiveness of Oral Cholera Vaccine in reducing cholera related mortality in the hotspot zones of Lusaka District, with a goal to inform public health strategies for cholera prevention and control. Methods: Retrospective cross-sectional study from April 2022 to April 2024, among 385 reported cholera cases meeting clinical/laboratory definitions in high-risk sub-districts (Kanyama, Matero, Mandevu, Chawama) on the effectiveness of the Oral Cholera Vaccine. Data was collected from health facilities, and surveillance databases. Descriptive statistics, and multivariable regression analysis were performed to evaluate the association between the independent variables and the outcome at a P value less than 0.05 with 95% confidence interval (CI). Results: Among the 385 cases reported, only 59.2% of the participants were vaccinated. Vaccination reduced cholera severity (coefficient=0.815, p<0.001), while hospitalization worsened outcomes (-0.193, p<0.001). Longer hospital stays improved recovery (0.108, p<0.001). Older age (0.002, p=0.020) and male gender (0.066, p=0.026) were linked to better outcomes. Access to clean water (-0.051, p=0.099) and improved water sources (-0.077, p=0.001) reduced the risk of disease. Sanitation and geographic location had no significant effects. Conclusion: OCV had a significant reduction on mortality and disease severity during cholera outbreaks in the hotspot zones. The results affirm the role of OCV in cholera prevention and emphasize the need to expand vaccine coverage, improve WASH infrastructure, and tailor healthcare interventions based on demographic differences.