Background: In 2020, during the COVID-19 pandemic, Médecins Sans Frontières (MSF) initiated three cycles of dihydroartemisin-piperaquine (DHA-PQ) mass drug administration (MDA) for children aged three months to 15 years within Bossangoa sub-prefecture, Central African Republic. Coverage, clinical impact, and community members perspectives were evaluated to inform the use of MDAs in humanitarian emergencies. Methods: A household survey was undertaken after the MDA focusing on participation, recent illness among eligible children, and household satisfaction. Using routine surveillance data, the reduction during the MDA period compared to the same period of preceding two years in consultations, malaria diagnoses, malaria rapid diagnostic test (RDT) positivity in three MSF community healthcare facilities (HFs), and the reduction in severe malaria admissions at the regional hospital were estimated. Twenty-seven focus groups discussions (FGDs) with community members were conducted. Results: Overall coverage based on the MDA card or verbal report was 94.3% (95% confidence interval (CI): 86.3–97.8%). Among participants of the household survey, 2.6% (95% CI 1.6–40.3%) of round 3 MDA participants experienced illness in the preceding four weeks compared to 30.6% (95% CI 22.1–40.8%) of MDA non-participants. One community HF experienced a 54.5% (95% CI 50.8–57.9) reduction in consultations, a 73.7% (95% CI 70.5–76.5) reduction in malaria diagnoses, and 42.9% (95% CI 36.0–49.0) reduction in the proportion of positive RDTs among children under five. A second community HF experienced an increase in consultations (+ 15.1% (− 23.3 to 7.5)) and stable malaria diagnoses (4.2% (3.9–11.6)). A third community HF experienced an increase in consultations (+ 41.1% (95% CI 51.2–31.8) and malaria diagnoses (+ 37.3% (95% CI 47.4–27.9)). There were a 25.2% (95% CI 2.0–42.8) reduction in hospital admissions with severe malaria among children under five from the MDA area. FGDs revealed community members perceived less illness among children because of the MDA, as well as fewer hospitalizations. Other indirect benefits such as reduced household expenditure on healthcare were also described. Conclusion: The MDA achieved high coverage and community acceptance. While some positive health impact was observed, it was resource intensive, particularly in this rural context. The priority for malaria control in humanitarian contexts should remain diagnosis and treatment. MDA may be additional tool where the context supports its implementation.