Lumpy skin disease (LSD) is an acute viral disease of cattle that is currently emerging in the Middle East region and poses a serious threat to Europe and the rest of the world. The objective of this study was to describe hematological and serum biochemical findings associated with natural clinical infection of LSD in cattle. A total of 129 animals clinically infected with LSD were enrolled in the study. Venous blood sample were collected from study animals, and hematological and serum biochemical parameters were measured. Leukocytopenia was found in 8.7%, while leucocytosis was found in 18.2% of affected cattle. Decreased hematocrit concentration was seen in 18.3%. Most affected cattle had reduced mean corpuscular volume (43.7%), mean corpuscular hemoglobin (14.3%), and mean corpuscular hemoglobin concentration (11.5%). All cattle with abnormal platelets count had thrombocytopenia. Hyperfibrinogenemia, hyperproteinemia, and hyperalbuminemia were found in 69%, 59.6%, and 37.2% of affected cattle, respectively. Decreased creatinine concentration was seen in 65.8%. Hyperkalemia and hyperchloremia was found in 9.6% and 10.4% of the affected cattle, respectively. LSD appears to be associated with inflammatory leukogram, anemia, thrombocytopenia, hyperfibrinogenemia, hyperproteinemia, decreased creatinine concentration, hyperchloramia, and hyperkalemia. These are likely due to the associated severe inflammatory process and disease complications such as anorexia and reduced muscle mass. This is the first study that documents hematological and serum biochemical findings associated with LSD infection. Understanding the blood profile picture may give further insight to the pathogenesis of the disease and help in treatment of individual cattle.