The Great Lakes strain of viral haemorrhagic septicaemia virus (VHSV) isolated from adult subclinical muskellunge, Esox masquinongy days post‐infection (p.i.). The median lethal intraperitoneal injection dose (IP‐LD days after exposure in waterborne challenged fish, whereas fish infected by the i.p. route experienced the first mortality by 5 (Mitchill), in Lake St. Clair, MI, USA was shown to be highly pathogenic in juvenile muskellunge through intraperitoneal (i.p.) injection and waterborne challenge. Mortality began as early as 350) was approximately 2.21 plaque forming units (PFU) as opposed to the median lethal immersion challenge dose (IM‐LD5010 × ) of 1.74mL PFU −1. A high, medium and low dose of infection caused acute, subacute and chronic progression of the disease, respectively, as was evident by the cumulative mortality data. Clinical signs of disease observed in dead and moribund fish were very pale gills, dermal petechial haemorrhages along the flanks, severe nuchal haemorrhages, intramuscular haemorrhages at the fin–muscle junction and focal haemorrhaging on the caudal peduncle. Internal lesions included livers that were pale, discoloured and friable, and kidneys that were either congested or degenerative in appearance, and petechial to ecchymotic haemorrhages on the swim bladder wall. Histopathologic examination demonstrated massive haemorrhages in the swimbladder wall and muscle, severe vacuolation and multifocal necrosis of the liver, multifocal necrosis of the gills and depletion of lymphoid tissues within the spleen. Kidney tissues also exhibited a mixed pattern of degeneration that included tubular necrosis, interstitial oedema and congestion. Virus was recovered from kidney and spleen tissues through tissue culture and reverse transcriptase‐polymerase chain reaction (RT‐PCR).