Effectively communicating health knowledge plays a significant role in promoting health behavior. Messages could be framed to highlight either the benefits of engaging (gain-framed) or the consequences of not engaging (loss-framed) in particular health behavior, yet existing studies have identified mixed findings regarding the impact of gain-framed vs. loss-framed messages. Drawing upon prospect theory and construal level theory, we first examine how gain-framed vs. loss-framed messages affect health knowledge adoption. Then, we investigate how gain- (loss-) framed messages should be paired with psychological distance (proximal vs. distal) to enhance one’s processing fluency, which functions as a mediator to influence health knowledge adoption. We conducted two between-subjects experiments. The findings of this research have implications for designing effective public health communication and health information services.