BACKGROUND: Rodent-borne viruses, including hantaviruses, arenaviruses, and rodent hepatitis virus (HEV-C), pose significant health threats to humans, causing severe diseases such as hepatitis, respiratory illness, and hemorrhagic fevers. In Cambodia, data on these viruses remain limited, and their burdens on human health are unknown. This study investigated the presences of these viruses in rodents and assessed potential human exposure across diverse environmental and socio-economic contexts in Cambodia. METHODS: The study was conducted in urban, semi-urban, and rural areas of Cambodia during the rainy (2020) and dry seasons (2022). Rodents were screened for arenavirus, hantavirus, and HEV-C using RT-PCR. Human serum samples from the same site were tested for IgG antibodies using ELISA. Factors associated with virus spillover into humans were analyzed. FINDINGS: Among 750 rodents, 9.7% carried at least one virus: 5.2% arenavirus, 3.3% hantavirus, and 1.9% HEV-C. Infection rates were highest in urban (14.5%), followed by semi-urban (11.9%) and rural (2.1%) interfaces. Arenavirus was more prevalent during the rainy season, while hantavirus and HEV-C remained consistent across seasons. Seroprevalence in human was 12.7% for arenavirus, 10.0% for hantavirus, and 24.2% for HEV. Higher arenavirus seroprevalence was associated with urban recidency and lower education level. Hantavirus seroprevalence was associated with urban residency, acute hepatitis history, and flood-prone living areas. HEV seroprevalence increased with urban residency, increasing age, and medical condition history. INTERPRETATION: Our findings highlighted the need for rodent control, improved market infrastructure, enhanced waste management, and public awareness on hygiene practices and zoonotic risks, especially in urban and high-risk areas.