Home-based care messages were part of behavioral modification interventions to mitigate COVID-19 spread early in the pandemic. What remains unclear is the types of home-based care knowledge people have and whether different kinds of home-based care knowledge influence a person's self-efficacy and response efficacy in managing mild cases. Using a cross-sectional online survey, this exploratory study investigated differences in biomedical and alternative knowledge about COVID-19 home-based care and their association with self and response efficacy from respondents in Ghana and the US. With a total sample of 736 made up of 50.3% from Ghana and 49.7% from the US, the average age range was of 39-48 years. Sixty two percent were females and 38% males. Using chi-square goodness of fit tests, t-tests, and multiple regression for analysis, we found that US respondents had higher biomedical knowledge while Ghanaian respondents had higher alternative knowledge. Although self-efficacy and response efficacy were high in both countries, both kinds of knowledge did not independently improve respondents' self-efficacy or response efficacy. However, a combination of biomedical and alternative home-based care knowledge items predicted self and response efficacy. Health promoters need to consider ways of utilizing both knowledge types in a complimentary manner during disease outbreaks.