The Nile tilapia (Oreochromis niloticus) and the African sharptooth catfish (Clarias gariepinus) are the most widely cultivated fish species in Egypt. The production cycle runs from spring to autumn, during which water temperatures are conducive to fish growth and the propagation of leeches, which transmit fish hemoflagellates (Trypanosoma spp.). A total of 710 Nile tilapia and 385 catfish were randomly collected from three different sites—two private farms and Burullus Lake—throughout the year. Fish blood samples were examined for Trypanosoma infection. Regardless of fish species or collection site, the highest infection rate of T. mukasai was observed during summer. The catfish samples showed a higher infection rate than the Nile tilapia, and fish farms had higher infection rates compared to Burullus Lake. A positive correlation was found between Trypanosoma infection and water temperature, nitrogenous compounds (unionized ammonia, nitrite, and nitrate), total bacterial count (TBC), and total coliform count (TCC). Based on these findings, Trypanosoma infection can be expected during the production cycle (spring to autumn), and it is recommended to maintain optimal water parameters to prevent conditions favorable to infectious agents.