The present study was performed to investigate the cross-talk interactions of hematological profile, minerals and electrolytes concentrations and determine the histopathological variations associated with pneumonia in sheep. Fifty adult sheep were examined and divided into healthy (n = 20) and pneumonic sheep (n = 30). Pneumonia was confirmed by clinical and histopathological examinations in sheep. Liver, kidney function tests and mineral profile were colorimetrically determined via spectrophotometer by the method specified. Serum calcium, phosphorus, sodium and chloride concentrations were decreased in pneumonic sheep compared to healthy ones (P < 0.05). Additionally, the mean values of red blood cells (RBCS), hemoglobin (Hb), and packed cell volume (PCV) were significantly reduced while, the mean value of white blood cells (WBCS) and neutrophils were significantly increased in pneumonic sheep compared to healthy sheep (P < 0.05). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine and potassium concentrations were significantly increased in pneumonic sheep than healthy ones (P < 0.05). Lung histopathology revealed interalveolar septal thickening with vascular congestion, hydropic degeneration of bronchiolar mucosa, and lymphocytic infiltration. It was concluded that, pneumonic sheep were associated with altered hematological, minerals and electrolytes parameters. Decreased phosphorus concentrations could also be involved in the pathogenesis of erythrogram count. Hyperkalemia is associated with hyponatremia in pneumonic sheep.