Background: Low health literacy is associated with poor health status, poor self-management, and poor use of healthcare. This study assessed the associations of caregivers’ health literacy, incidence of malaria in children, use of healthcare and associated household costs in the management of malaria in children under five years.Method: This is a cross-sectional study with data (N=1270) collected in November - December 2017. We used hierarchical cluster analysis to generate health literacy profiles of caregivers based on responses to the Health Literacy Questionnaire (HLQ). We run logistic regression models and generalized linear models with incidence of malaria, desirable use of healthcare and household costs as dependent variables, and health literacy profiles and other socio-demographic and access variables as covariates. Results: We generated 7 caregiver health literacy profiles with Profile 1 characterised by overall high scores, Profile 4 by overall moderate scores and Profile 7 by overall low scores on nine health literacy dimensions. With Profile 4 as reference, children of caregivers in Profile 7 had 69% increased odds of an incident of malaria and no difference in odds for those of Profile 1. Profiles 1 and 7 both had reduced odds of desirable use of healthcare, 26% and 58% respectively. Caregivers in Profile 1 incurred higher spending, while caregivers in Profile 7 incurred lower spending on management of malaria in children as compared to Profile 4. Conclusions: Our findings suggest that general health literacy of caregivers as measured by the HLQ may not be influential in incidence of malaria, desirable use of healthcare and household costs in the management of malaria in children under five years in Ghana where malaria is highly prevalent. The use of hierarchical cluster analysis was feasible in the analysis of comprehensive health literacy and facilitated analysis on use of healthcare and associated costs.