Public opinion polls have historically indicated that the US public favours domestic over global priorities. It is not known what influence health knowledge has in shaping public opinion about domestic and global health policy. This study examines how knowledge of HIV/AIDS is related to the rated importance of domestic and global health issues. Participants were recruited to participate in an electronic survey (N = 995) and were predominantly White (86.3%), married (61.9%) and female (71.8%). HIV/AIDS knowledge was significantly associated with both domestic (β = 0.12, p < 0.05) and global health (β = 0.14, p < 0.01) priorities after controlling for sociodemographic variables. In addition, global health was found to act as a mediator between HIV/AIDS knowledge and perceived importance of domestic issues. Study findings suggest that those with greater HIV/AIDS knowledge rate global health issues higher, which in turn affects ratings of more domestic issues. This research has implications for ways to gain support for implementation of public health policy through increasing health knowledge.