The goals of this study were to determine serum protein fractions, acute phase proteins and inflammatory cytokine concentrations, as well as histological alterations, phagocytic activity, and index in sheep with pneumonia. An overall 50 adult sheep were assessed and categorized into control healthy (Group 1, n=20), and sheep with acute pneumonia (Group 2, n = 30). Pneumonia is medically diagnosed by physical examinations, ultrasonography, as well as histopathological investigation. Serum protein fraction concentrations were measured by protein electrophoresis, while inflammatory biomarkers were measured by immunoassays. Concentrations of serum total protein, globulins, 1α-globulins, β-globulins, γ-globulins, immunoglobulin G, immunoglobulin M, haptoglobin, serum amyloid A, and inflammatory cytokines (Interleukin-1β, interleukin-6, and tumor necrosis factor-α) were significantly increased while albumin and Interleukin-10 were decreased in acute pneumonic group than healthy group. Phagocytic activity and index were significantly decreased in diseased sheep compared to healthy control ones. Histopathological examination of lung tissues revealed thickening of interalveolar septa, congestion, alveolar hemorrhages, hemosiderophages, and lymphocytes and macrophages infiltration. In conclusion, acute pneumonia is associated with a severe pro-inflammatory condition that enhances the release of inflammatory cytokines, resulting in organ dysfunction and mortality in sheep. With strong sensitivity and specificity, serum haptoglobin and serum amyloid A concentrations act as diagnostic biomarkers for pneumonia in sheep.