Child malnutrition remains a public health challenge in developing countries, but a comprehensive understanding of its burden and its determinants in specific local contexts is generally lacking. This study examined the prevalence of malnutrition and its determinants among children aged <5 years across contrasting agroecosystems in northwest Ethiopia. A community-based cross-sectional study involving 400 respondents was employed. Data were collected through semi-structured questionnaires and anthropometric measurements, complemented with focus group discussions and key informant interviews. The direct and indirect effects of the determinants of malnutrition were examined using structural equation modeling (SEM). The overall prevalence of child malnutrition, measured using the Composite Index of Anthropometric Failure, was 49%, with notable variation across agroecosystems (from 36.1% [midland with red soil] to 59% [lowland and valley fragmented]). Disease experience had significant positive direct effects on malnutrition. Dietary intake had negative and significant total (direct and indirect) effects on malnutrition, partially mediated through disease experience. Serial mediation in SEM analysis revealed significant indirect relationships between malnutrition and food security, feeding and care practices, household environment, health services, maternal diet, maternal empowerment, household wealth, and nutrition-sensitive agricultural practices. In conclusion, child malnutrition was highly prevalent and higher among children in the lowland and valley fragmented agroecosystem, characterized by unfavorable agro-climatic conditions, lower wealth status, poor health services access, and higher disease (particularly malaria) exposure. This study demonstrates the dynamics and multifaceted nature of malnutrition, highlighting the importance of considering geographical differences when planning interventions for childhood malnutrition and its determinants.