Hematology and histopathological variations in Clarias gariepinus sub-adults subjected to oral challenge with Pseudomonas aeruginosa ATCC27853 were studied for a period of 21 days, with a view to assess the pathogenesis of the bacteria and compared with a control. The results were compared statistically using One-way ANOVA. The symptoms of the infected fish included tail and fin rot, internal hemorrhages and skin patches of superficial ulcers. Tissue sections revealed marked loss and sloughing off of the gill lamellar epithelium, liver showed that hepatocytes appear finely reticulated and foamy; however there were a few foci of large cytoplasmic vacuolations of the hepatocytes and the sinusoids were moderately congested while the intestine showed shortened rugae; the submucosa glands were reduced in numbers; however the surface epithelial cells appeared to be proliferating rapidly and immature (hyperplastic). There was a significant reduction in the mean values of packed cell volume from 34.67±5.2% to 22.33±0.3%, hemoglobin from 9.77±0.2g/dL to 6.97±0.2g/dL, red blood cell from 2.23±0.3x1012/L to 1.27±0.1 x1012/L and lymphocyte count from 69.00±2.3% to 52.33±0.9% of C. gariepinus after three weeks of exposure to P. aeruginosa. However, the reverse was the case in the mean values obtained for white blood cell and neutrophil for infected fish which were reasonably higher when compared to that of uninfected fish (17.13±0.5 to10.80±0.3x109/L) and (47.33±1.2% to 30.33±2.9%) respectively. It could therefore be concluded that changes in organs and blood parameters of fish occur proportionately to pathogen invasion.