Streptococcosis became one of the most dangerous bacterial diseases affects cultured marine and freshwater fish. In the present study Streptococcus iniae was isolated from diseased Nile tilapia (Oreochromis niloticus) with investigation of the clinical signs, post mortem lesions and focusing on the histopathological changes in liver and kidney using the light and Transmission Electron Microscope (TEM). Natural infected O. niloticus showed ascites, exophthalmia, presence of hemorrhagic patches all over the external body surface with inflammation and swelling of the anal opening. Post-mortem examination indicated presence of hepatomegaly, splenomegaly, congestion and swelling of posterior kidney. Four Streptococcus iniae isolates were recovered and identified using PCR from the examined fish. The LD_50-96h of the recovered isolates in experimentally infected Oreochromis niloticus were ranged between 0.2 ml of  2.62 – 3 × 10⁷ CFU/ml by intraperitoneal injection. Under the light microscopical examination, severe degenerative changes were present in the hepatopancreas including diffused hepatic cell vacuolation and necrosis, leukocytic infiltration, the posterior kidney tissue showed vacuolation of tubular epithelial cells, shrinkage of glomerular taught and increasing the Bowman''s space. TEM examination of hepatopancreas revealed the presence of hepatocellular degeneration, increased vacuolation in the different areas of the cytoplasm, loss of endoplasmic reticulum contact in several areas. Kidney tissues showed numerous vacuolation, swollen of cuboidal epithelial cell with absence of brush border in the apical portion of the proximal convoluted tubules, nucleus and mitochondria were dispersed throughout the cytoplasm.