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This study investigated the knowledge of Artemisinin Combination Therapy (ACT) and malaria status of inhabitants of a malaria endemic region and also determined if ACT use confers a reduction in malaria outcome. A cross-sectional study was conducted in Ilorin metropolis, North-Central Nigeria. Quantification of malaria parasite in venous blood was carried out using Giemsa-stained thick blood film. Respondent’s bio-data, socio-demographic factors, knowledge of malaria and ACTs were obtained using a pre-tested questionnaire. Two hundred and nine participants (68; 32.5% males and 141; 67.5% females) were recruited for the study. Malaria prevalence increased with increasing age; viz; 35-45 years (70.4%) with a remarkable decline (51.0%) at age-group >45years. Educational status significantly correlated with infection rate (p=0.09). Large family size and resting together at night were determinants of disease occurrence (p>0.05). Knowledge of malaria and ACTs among respondents was 96.7% and 65.6% respectively. Knowledge of ACT significantly differed with knowledge of malaria and its mode of transmission (p<0.05). Knowledge of ACT was not dependent on gender, age-group, ethnicity, occupation, family size and resting at night together. However, this was comparable among those with complete secondary education (67.1%), primary education (65.2%) and illiterates (56.8%) (p<0.05). Malaria prevalence among respondents who had knowledge of ACT was higher (57.7%) compared to those who do not (54.2%; p>0.05). Knowledge of ACTs and infection intensities revealed that more respondents with adequate knowledge of ACT were moderately infected (54.4%), likewise for participants with dearth of ACT knowledge (41.0%; p=0.223). Prevalence of infection based on the choice of ACT indicated a least prevalence (42.9%) among those that used a combination of artemethermefloquine and artemether-lumefantrine, compared to artemether-mefloquine (60.4%) and artemetherlumefantrine (57.4%; p=0.714). Despite the vague knowledge of ACT use and its importance in malaria therapy, the disease still persists in this region. The perceived knowledge is insignificant, mass awareness is encouraged and self-medication should be discouraged. Keywords: Malaria, Knowledge, Artemisinin Combination Therapy, North Central, Nigeria.