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Vaccination is one of the essential measures in reducing transmission, morbidity, and mortality rates of a disease. However, the COVID-19 vaccination is facing hesitancy across the globe, Malawi included. A population-based cross-sectional study was conducted in Malawi to document knowledge, attitudes, and practices on COVID-19 vaccination. The study targeted the general adult population and employed a multi-stage sampling technique. The Census Enumeration Areas within the 16 selected districts served as a primary sampling unit. Among the total 3068 participants, 1947 (63.6%) were female. About 1039 (34.1%) participants had primary education, while only 169 (5.5%) had college education. A total of 2936 (95.7%) participants knew about the COVID-19 vaccine, and 2063 (68.4%) felt that the COVID-19 vaccine was effective. A total of 1180 (38.7%) got vaccinated. Knowledge of the COVID-19 vaccination was significantly associated with participants’ education levels, location, occupation, marital status, household family income, and whether they were suffering from chronic illness or not. Overall, the level of knowledge and attitudes about the COVID-19 vaccination was good. This study has also established that different population groups have statistically different levels of knowledge and attitudes regarding COVID-19 vaccination. This study has also indicated a significant relationship between the rate of vaccination and several factors. Therefore, this calls for stakeholders to continue awareness and group-targeted tailored campaigns so as to increase COVID-19 vaccination.