Marine diseases have major impacts on ecosystems and economic consequences for aquaculture and fisheries. Understanding origin, spread and risk factors of disease is crucial for management, but data in the ocean are limited compared to the terrestrial environment. Here we investigated how the marine environment drives the spread of viral disease outbreak affecting The Pacific oyster worldwide by using a spatial epidemiology framework. We collected environmental and oyster health data at 46 sites spread over an area of 300 km2 along an inshore-offshore gradient during an epizootic event and conducted risk analysis. We found that disease broke out in the intertidal farming area and spread seaward. Mortalities and virus detection were observed in oysters placed 2 km from the farming areas, but oysters of almost all sites were subclinically infected. Increasing food quantity and quality, growth rate and energy reserves of oyster were associated with a lower risk of mortality offshore whereas increasing turbidity, a proxy of the concentration of suspended particulate matter, and terrestrial inputs, inferred from fatty acid composition of oysters, were associated with a higher risk of mortality. Offshore farming and maintenance of good ecological status of coastal waters are options to limit disease risk in oysters.