This study was performed to investigate the alterations that associated with experimental infection of Nile tilapia with Streptococcus iniae (S. iniae), Candida albicans (C. albicans) or their combination. The experimentally infected fish were carefully observed for four weeks for any clinical abnormalities, mortality rates, postmortem changes, biochemical and histopathological changes. The highest mortality rate, severe clinical signs and postmortem changes occurred in Nile tilapia fish in the S. iniae+ C. albicans infected group. There were significant changes in the evaluated biochemical parameters in all infected groups that were marked in the S. iniae-and the S. iniae+ C. albicans-infected groups. Specimens were collected from gills, liver, kidney, spleen, brain and intestine for histopathological examination. The lesions were variable among the infected groups, however; lesions intensity was more pronounced in fish infected with both pathogens. The present study established the synergistic interaction between S. iniae and C. albicans in Nile tilapia on the bases of clinical signs, mortality rates, postmortem changes, biochemical and histopathological changes.