Background Preventive chemotherapy targeting school-aged children has substantially reduced schistosomiasis morbidity, however, a key strategic tension remains between sustaining morbidity control and pursuing transmission elimination, particularly in settings characterised by heterogeneous transmission dynamics and persistent adult infection reservoirs. We developed a health system-integrated transmission and economic evaluation framework to identify optimal age-targeting and district-level prioritisation, providing a basis for determining when elimination-focused approaches offer advantages over morbidity reduction alone. Methods The Thanzi la Onse individual-based model was used to evaluate alternative age-targeted mass drug administration (MDA) strategies for Schistosoma haematobium and Schistosoma mansoni across all 32 districts of Malawi from 2024-2050. Strategies included treatment of school-aged children (MDA-SAC), pre-school and school-aged children (MDA-PSAC+SAC), and community-wide treatment (all ages). Health outcomes included person-years with any infection (PY), disability-adjusted life years (DALYs), probability of elimination (defined as reaching <2% prevalence of infection in all ages). The cost-effectiveness was evaluated using incremental cost-effectiveness ratios (ICERs), net health benefit (NHB), and by quantifying the maximum costs available for implementation, using a cost-effectiveness threshld for Malawi of 88 USD per DALY averted. Findings In the absence of MDA, the majority of the infection burden over 2024-2050 would be concentrated in adults aged 15 years and older (219.6 million person-years [PY], 95% CI 215.4-223.4), compared with 72.8 million PY (95% CI 71.5-74.3) among school-aged children (SAC) and 25.5 million PY (95% CI 25.1-26.2) among preschool-aged children. Annual MDA-SAC would avert approximately 18.0 million DALYs (95% CI 17.6-18.4) between 2025 and 2050 and would be highly cost-effective nationally (ICER 4.76 USD/DALY, 95% CI 4.47-4.95). Across districts, ICERs were highly variable; 25 of 32 districts were cost-effective in ≥90% of runs and 29 of 32 in ≥50% of runs. Expanding treatment to include preschool-aged children (MDA PSAC+SAC) would produce modest additional gains (additional 44,500 DALYs averted) but with substantially higher costs (national ICER 606 USD/DALY, 95% CI 472-695), being dominated in 22 districts and cost-effective only in the high-burden Likoma district. Community-wide MDA would achieve elimination for both species in all districts by 2030 and avert a further 98,000 DALYs; nationally it would be cost-saving relative to PSAC+SAC although outcomes were heterogeneous, with this strategy being cost-saving in 11 high-prevalence districts (2023 prevalence range 13.7 - 41.5%) but dominated (in >80% of model runs) in 16 others. Threshold analyses of maximum implementation costs indicated substantial cost margins in high-burden districts, with cost-effectiveness maintained up to approximately 25-38 USD per treatment. Interpretation The choice of schistosomiasis strategies should depend on whether programmes prioritise short-term morbidity reduction or long-term elimination, as well as the local disease burden and the prevailing cost of service delivery. Integrating district-level transmission dynamics with opportunity-cost-based economic evaluation reveals when broader coverage is justified and provides a framework for designing fiscally grounded elimination pathways in heterogeneous endemic settings.

The authors have declared no competing interest.

This study was supported by funding received from the Global Institute for Disease Elimination (GLIDE) as part of the Thanzi Labwino (Better Health) research project. The Thanzi la Mawa project is funded by Wellcome (223120/Z/21/Z). TM, RMW, BS and TBH acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/X020258/1) along with funding through Community Jameel.

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