Serious game can potentially improve social awareness and health literacy related to the epidemic, where interactivity, such as strategic game elements, could play a crucial role in increasing learning engagement and motivation. In this paper, we present the user study of InfecBlock, a tower-defense game designed to facilitate individual users to acquire public health knowledge related to coronavirus disease and epidemic prevention. We employed a between-subject experiment design and collected a variety of quantitative data to examine players’ learning outcomes, engagement, and emotional responses. Our results confirmed the effectiveness of InfecBlock in improving learning performance and highlighted its potential to facilitate a more engaged and enjoyable learning experience. We discussed a set of implications for designing tower-defense serious games for supporting the improvements of public health literacy.