Background:Health literacy is the ability to access, understand, and use health information for enhancing health. Health literacy research has led to the understanding of its associations with health outcomes and health-promoting behavior. Health literacy is essential to health promotion, but a gap exists in the knowledge of health literacy in Ghana, especially among university students.Objective:This study aimed to ascertain the levels of health literacy and its sociodemographic determinants among undergraduate university students of Kwame Nkrumah University of Science and Technology.Methods:A cross-sectional survey was conducted using multistage cluster sampling to select 500 students from six colleges of the University; of those, 485 were included for data analysis after exclusions. Health literacy was assessed using the 16-item short version of the European Consortium for Health Literacy Questionnaire.Key Results:About 55% of students were found to have limited health literacy (20.4% had “inadequate” health and 34.2% had “problematic” health literacy). Students performed low on health literacy dimensions dealing with the access and appraisal of health information, especially relating to mental health. Multivariate logistic regression showed that factors associated with limited health literacy differed for each gender but generally included college type, self-esteem, health status, and year of study.Conclusions:Interventions need to be implemented to improve students' health literacy. [HLRP: Health Literacy Research and Practice. 2019;3(4):e227–e237.]Plain Language Summary:The study reveals that health literacy may be a challenge even for the educated in Ghana especially among vulnerable people. University students should not be assumed to be health-literate and interventions that will help enhance their literacy in health should be implemented.