Rabies is a highly fatal and transmissible zoonotic disease, causing approximately 59,000 human deaths each year across more than 150 countries, with over 95% of cases occurring in Asia and Africa and imposing a substantial public health burden. It remains one of the most serious dog-mediated zoonoses in both China and Zambia. In Zambia, periodic outbreaks are driven by domestic dogs as the principal reservoir, placing rural children at especially high risk, while inland provinces of China continue to experience dog-mediated rabies incidence. Beyond rabies, emerging threats such as blood-borne pathogens lack systematic quantification. This study provides a direct epidemiological comparison between the two countries to inform targeted interventions. The study employed mixed methods, including a quota-sampled, cross-sectional observational survey based on the Knowledge, Attitudes, and Practices (KAP) framework and focus group discussions (n = 39), surveying residents in Hainan (n = 2,388) and Mambwe (n = 433). While most participants held positive attitudes toward rabies, significant gaps emerged in both knowledge and practice. Common deficits included (1) a lack of awareness that rabies is incurable, (2) insufficient knowledge regarding the transmission pathways of rabies, and (3) limited understanding of the risks posed by seemingly healthy dogs. In Mambwe specifically, additional issues were identified: (4) low coverage of dog registration and vaccination and (5) widespread practices of free-roaming dog ownership. To control and ultimately eliminate rabies, we recommend context‐specific strategies: (1) enforcing strict boundaries between human settlements and wildlife conservation areas; (2) investing in rural infrastructure; (3) enhancing community engagement; and (4) adopting One Health approach. In Mambwe District, blood samples were collected from 277 domestic dogs owned by farmers living adjacent to the national park boundary. Metagenomic sequencing using Oxford Nanopore Technologies revealed six pathogenic microbial species or subspecies: Anaplasma platys, Ehrlichia canis, Pasteurella multocida, Trypanosoma congolense IL3000, Trypanosoma brucei, and Trypanosoma brucei brucei. These pathogens pose significant cross‐species transmission and zoonotic spillover risks, threatening human health, livestock productivity, and wildlife conservation. Notably, Pasteurella multocida was detected in Zambian dogs for the first time. These findings provide detailed insight into the role of domestic dogs within this distinctive agricultural system and establish a scientific foundation for future One Health management strategies and policy development. They are expected to inform the refinement of rabies policies and targeted control measures in Asia and Africa, thereby supporting the prevention of dog‐associated diseases.