Knowledge, attitudes, and practices (KAP) surveys on malaria and antimalarial mass drug administration (MDA) have not received much attention in the Union of the Comoros. This study is a household-based cross-sectional survey using a multi-stage sampling technique aiming at investigating KAP toward malaria and antimalarial MDA with artemisinin-piperaquine among heads of households on Grande Comore Island, the largest island of the Comoros. A predefined structured questionnaire containing socio-demographic characteristics and questions about malaria and antimalarial MDA was administered to 1,368 randomly selected heads of households from 10 malaria-endemic villages on Grande Comore Island. The results showed that 81.4% of the heads of households knew that malaria is a transmissible disease, 77.6% recognized mosquitoes as the vectors of malaria, and 70.8% recognized fever as one of the frequent symptoms of malaria; 40.8% of respondents remembered the name of the antimalarial drug used for MDA, and 62.1% remembered the color of the antimalarial tablets; and 65.1% chose to go to a public health center to seek treatment as their first option within 24 hr of the onset of initial malaria symptoms. This study found that most heads of households had a reasonable level of knowledge about malaria and antimalarial MDA. However, only 7.3% obtained full points on all knowledge-related questions. Misconceptions about malaria cause, transmission, diagnostic method, and antimalarial MDA exist in the community of Grande Comore Island. As the Comoros continues to put great efforts to go toward malaria elimination, the community's KAP on malaria and antimalarial MDA is crucial to guarantee the community's long-term adherence to malaria elimination interventions and could become key to guaranteeing malarial elimination in the Comoros. Therefore, there is a great need to improve malaria prevention awareness through strengthening malaria education and promoting behavioral change. Heads of households should be the core target of malaria education and behavioral change for malaria elimination.