Bluetongue (BT) is an economically important contagious viral disease transmitted by insect vectors of Culicoides species affecting both domestic and wild ruminants caused by Genus Orbivirus of Reoviridae family. Present in vivo study for the first time conducted to understand the role of oxidative stress and acute phase proteins in the pathogenesis of endothelial injury in target blood vessels of BTV-4 infected sheep. Twelve sheep of either sex were divided into two groups of six animals each and infected intradermally at multiple sites in the neck region with 6×10^5.9 TCID₅₀/ml of BTV-4 and animals of control group were inoculated with uninfected tissue culture fluid. Animals were sacrificed at 3, 7, 15, 28, 60, and 90 days post infection (dpi) and postmortem examination was conducted. Oxidative stress parameters like LPO, SOD, GPO and catalase in the blood vessels, hemolysate and serum were estimated. Oxidative stress parameter like LPO was upregulated and anti-oxidant parameters like SOD and GPO were downregulated in blood vessels homogenates, hemolysate and serum of BTV-4 infected animals than uninfected control. This shows the role of oxidative stress in causing endothelial cell damage during BTV infection. Acute phase proteins like CRP and fibrinogen in serum and plasma were estimated and found upregulated in BTV-4 infected animals, which shows that inflammatory changes during the disease causes vascular damage. Prothrombin time was estimated in plasma of BTV-4 infected animals and was prolonged in BTV infected animals indicating coagulation disorder. Increased oxidative stress and fibrinogen, and prolonged prothrombin time indicated the coagulation disorders induced by BTV infection by causing endothelial cell damage and severe vascular disease results in congestion, haemorrhages and edema in the blood vessels and other target organs in sheep.