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Introduction Health literacy refers to acquiring and utilizing health information to make health-related actions and decisions. Filipino domestic workers with low health literacy are often vulnerable to health problems due to poor living and working conditions. Objective This study examined the effect of an online health literacy promotion program on health literacy and health knowledge of Filipino domestic workers in Macao. Methods The mixed method combined quantitative findings of a quasi-experimental study with qualitative results applied. The quasi-experiment included three parallel groups: a synchronous online education group (videoconference group), an asynchronous online education group (video group), and a control group. A total of 88 Filipino domestic workers were assigned to one of these groups, and eight respondents participated in two focus-group interviews respectively after the intervention. Results For quantitative data, both synchronous and asynchronous online education interventions had positive effects. While comparing with the control group, participants in the videoconference group were more likely to have better health promotion health literacy after the intervention (β = 5.36, p = .02), and participants in the video group were more likely to have better general health literacy (β = 5.17, p = .01), disease prevention health literacy (β = 5.31, p = .04), health promotion health literacy (β = 5.97, p = .01). For qualitative data, three themes and eight subthemes were extracted after the online health literacy promotion program. After integrating the findings of this study, the study found that this program was essential and beneficial for Filipino domestic workers’ health knowledge and health literacy. Conclusion Overall, online health literacy promotion programe had positive impacts on participants revealed in this study. Asynchronous online education has made significant progress in overall health literacy, which may be more suitable as a widely promoted education method because of the characteristics and working conditions of this population.