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Background Tuberculosis preventive therapy (TPT) is critical in interrupting progression to disease, transmission and reducing incidence rates. Nonetheless, high costs have been barriers towards the expansion of shorter patient-friendly drug regimens. In 2019, a Unitaid-led deal reduced rifapentine costs by over 70%, facilitating Brazil’s implementation of 3 months of rifapentine+isoniazid (3HP), a short-course TPT regimen, in its public health system. We evaluated the health and economic impact of Brazil’s implementation of this patient-friendly regimen for short-course TPT.Methods We analysed surveillance data on 171 174 individuals initiating TPT from January 2019 to December 2024. A mixed-effects spatiotemporal Bayesian model estimated quarterly TPT initiation trends under (1) observed 3HP rollout versus a no-3HP counterfactual (Q3 2021–Q4 2024) and (2) projected universal 3HP coverage (Q1 2025–Q4 2027) versus extended no-3HP adoption. Cost-effectiveness analysis quantified active tuberculosis (TB) cases and disability-adjusted life-years (DALYs) averted, alongside costs, incremental cost-effectiveness ratios, net monetary benefits (NMBs) and return on investment of TPT under each 3HP coverage scenario.Results From 2022 to 2024, 3HP scale-up produced 37 508.4 (95% credible intervals (CrIs) 31 405.2 to 43 631.6) additional TPT initiations, averted an estimated 15 002 DALYs (95% CrI 8985.6 to 21 031.15) and yielded NMBs of US$122.7 million (95% CrI US$63.8 to US$198.2 million). Under a proposed universal coverage (2025–2027), projected gains included 72 080.1 (95% CrI 62 323.7 to 81 836.4) additional individuals starting TPT, with subsequent 26 139 DALYs averted (95% CrI 14 117 to 38 762) and NMBs of US$214.5 million (95% CrI US$103.0 to US$362.8 million), indicating strong economic dominance over no-3HP adoption. Finally, TPT with 3HP’s implementation was estimated to return US$1.31 (95% CrI US$0.97 to US$1.62) to the health system for every US$1 invested.Conclusions In Brazil, large-scale implementation of a patient-friendly short-course regimen (3HP) was effective and likely cost-saving for a resource-strained public health system. Our evaluation provides robust, real-world evidence that implementing this regimen improved TPT coverage and completion nationwide while reducing costs and TB disease burden.