Background: Malaria remains a major public health problem in Africa. An estimated 300-500 million people suffer from malaria with 1.5-2.7 million deaths occurring yearly. Malaria remains a major killer of children in sub-Saharan Africa, claiming the life of a child every 2 minutes. Malaria among children under five is still major health problem, which is the leading cause of OPD attendance (21.5%) in the Yendi Municipality. Objective: The objective of the study was to determine the factors contributing to high prevalence of malaria in children under five in Yendi Municipality. Methodology: A hospital-based cross-sectional study was carried out with a quantitative data collection method. The sample size of 359 was obtained for this study. Data was entered into excel 2016 and SPSS Version 20.0. Chi-square test was performed to measure any association between independent and dependent variables. The predictors of malaria were identified using bivariate and multivariate logistic regression models. Variables which had P-values of <0.2 in the bivariate regression were included in the multivariable logistic regression analysis. A P-value <0.05 were considered to determine statistical significance. Finally, adjusted odds ratios (AOR) with a 95% confidence interval (CI) was used to determine the strength of association of variables. Findings: The prevalence of malaria among the children in this study was found to be 34.3%. Children whose caretakers attained tertiary level of formal education were 4.28 (95% CI: 1.15-15.98) times more likely to influence their malaria infection, compared to children whose caretakers were not having any form of formal education. In addition, respondents who were Kokombas were 2.14 (95% CI: 1.18-3.86) times more likely to be affected by malaria, compared to respondents who Dagbanlis. Moreover, respondents whose households’ size were 3 to 5 members were 2.10 times more likely to suffer from malaria as compared to households with size less than 3 (OR 2.10, 95% CI: 1.17-3.75). Respondents whose source of drinking water was from protected wells as well as other sources were 83% each less likely to experience malaria, compared to respondents who had their drinking water from surface water. The overall level of adherence of respondents to malaria prevention measures in this study indicated that majority (57.1%) of them did not adhere to the measures. Children who slept under treated bed nets were 88% less likely to be infected by malaria (AOR:0.12, 95%CI: 0.05-0.34), while children who took SMC drugs were 98% less likely to suffer from malaria (AOR:0.02, 95%CI: 0.00-0.21). Conclusion: The current study shows that the prevalence of malaria infection among children aged 6 to 59 months in Yendi Municipal was at 34.3%. This study identified that attaining tertiary education, belonging Kokomba ethnic group, family size of 3-5 increased the risk of malaria infection. However, source of water from well or other places other than open source, use of ITNs and intake of SMC drugs decreased the risks of malaria infection in this study.