Typhoon Rai (202122) was one of the most devastating natural disasters globally, and the Philippines is the country that was heavily hit by this super typhoon. This study examined the preparedness of Filipinos using a novel framework considering ergonomic domains and disaster knowledge. A total of 414 Filipinos in eight regions affected by the typhoon answered the online questionnaire distributed through social media sites using a convenience sampling approach. Ergonomic-based indicators for physical, cognitive, and macro-ergonomics were analyzed simultaneously with disaster-knowledge indicators such as awareness, adaptation, and risk perception. The results from the partial least square structural equation modeling (PLS-SEM) and artificial neural network (ANN) showed that physical ergonomics and macro-ergonomics are key factors affecting the perceived preparedness of Filipinos for Typhoon Rai (202122). Moreover, disaster awareness, adaptation, and risk perception were also found to positively influence the respondents’ perceived preparedness, while disaster awareness influenced adaptation and risk perception. The findings revealed that residents in highly exposed locations must practice typhoon preparation and evacuation ahead of time. The results of this study could be utilized to educate local communities about the importance of emergency response options during a typhoon to lessen the damage and risks associated with it. Academicians and disaster planners may extend the findings of this study to investigate the role of ergonomics and disaster knowledge in developing preparedness systems to increase resilience by strengthening emergency management knowledge, reinforcing coordination, and communication among communities, decreasing occupational dangers, and improving processes to improve response efficiency and effectiveness.