Pacific oyster Crassostrea gigas were inoculated with OsHV-1 at low load (control) or high load (challenged) to better understand the pathogenesis of ostreid herpesvirus 1 (OsHV-1 μVar) and to determine which metabolic pathways might be affected during infection. Animals were sampled for proteomic analysis two days post-injection, at the same time as OsHV-1 initiated an intense replication phase in challenged oysters. Twenty-five abundant protein spots that showed a marked change in accumulated levels were identified using a two-dimensional electrophoresis (2-DE) proteomic approach. Overall, these proteins are involved in cytoskeleton organization, protein turnover, induction of stress signals, signalling pathways and energy metabolism. Challenged oysters exhibited an increased glycolysis and VDAC accumulation, which reflect a “Warburg effect” as initially reported in cancer cells and more recently in shrimp infected with virus. The results presented here should be useful for identifying potential biomarkers of disease resistance and developing antiviral measures. Biological significance This study is the first 2-DE proteomic analysis dedicated to the pathogenesis of ostreid herpesvirus 1 (OsHV-1 μVar) in oyster Crassostrea gigas, the most important bivalve produced in the world. OsHV-1 has affected oysters every year since 2008. All the proteins identified in this paper are key targets involved in OsHV-1 infection processes. We presented evidence that the metabolic changes during infection in oyster somehow resemble the Warburg effect occurring in cancer cells. This work constitutes a real advance in the comprehension of the host metabolic pathways affected during OsHV-1 disease. Overall, this work contributes to a better understanding of disease mortalities in aquatic ecosystems which could guide management actions to mitigate their impacts.