INTRODUCTION: Human papillomavirus (HPV) vaccination has not been introduced in many countries in South-Central Asia, including Afghanistan, despite the sub-region having the highest incidence rate of cervical cancer in Asia. This study estimates the potential health impact and cost-effectiveness of HPV vaccination in Afghanistan to inform national decision-making. METHOD: An Excel-based static cohort model was used to estimate the lifetime costs and health outcomes of vaccinating a single cohort of 9-year-old girls in the year 2018 with the bivalent HPV vaccine, compared to no vaccination. We also explored a scenario with a catch-up campaign for girls aged 10-14 years. Input parameters were based on local sources, published literature, or assumptions when no data was available. The primary outcome measure was the discounted cost per disability-adjusted life-year (DALY) averted, evaluated from both government and societal perspectives. RESULTS: Vaccinating a single cohort of 9-year-old girls against HPV in Afghanistan could avert 1718 cervical cancer cases, 125 hospitalizations, and 1612 deaths over the lifetime of the cohort. The incremental cost-effectiveness ratio was US$426 per DALY averted from the government perspective and US$400 per DALY averted from the societal perspective. The estimated annual cost of the HPV vaccination program (US$3,343,311) represents approximately 3.53% of the country's total immunization budget for 2018 or 0.13% of total health expenditures. CONCLUSION: In Afghanistan, HPV vaccine introduction targeting a single cohort is potentially cost-effective (0.7 times the GDP per capita of $586) from both the government and societal perspective with additional health benefits generated by a catch-up campaign, depending on the government's willingness to pay for the projected health outcomes.