French Guiana, France’s last malaria-endemic territory, has been facing an epidemic resurgence of malaria since late 2023. This epidemic, caused primarily by Plasmodium vivax, mainly affects populations living far from healthcare facilities. It has highlighted the challenges involved in delivering a full course of treatment. This treatment regimen includes both curative treatment using artemisinin derivatives (following the withdrawal of chloroquine from the market) and radical cure treatment with primaquine, with the challenge of ruling out G6PD deficiency. The objectives of this study are to describe the challenges of diagnosing and managing malaria in this unique region, to highlight the adaptations that have been made, and to propose diagnostic, therapeutic, and follow-up protocols tailored to the level of access to the healthcare system, with the aim of standardizing practices. This article also aims to highlight the innovative strategies implemented in French Guiana to address this new epidemic: health mediation, a mobile “malaria” team, rapid diagnostic tests and immediate off-site “Test and Treat” treatment, and the development of self-diagnosis and self-treatment. These proposals are part of a commitment to eliminate malaria in the short term within French territory.