This study investigates the prevalence, severity, and impacts of parasitic infestations in Clarias gariepinus. Additionally, the study assesses the detrimental impacts of parasite infestation on the health condition of affected catfish, focusing on biochemical and histopathological alterations. A total of 160 fish were sampled from local markets. Parasitological examinations involved the dissection of key organs from each fish. The organs were processed and examined microscopically for parasites identified based on morphometric characteristics. Parasitological indices such as prevalence, mean intensity, and abundance were calculated. Fish blood and liver samples were collected to assess hematological and biochemical parameters. Microscopic and ultrastructural examinations identified the gills and liver as highly infected organs, so they were utilized for transmission electron microscopy (TEM). Analysis of catfish tissues unveiled the existence of Cyathocotylid sp. and Prohemistomum vivax, across all organs with dominance noted in the liver, emphasizing their pathogenic significance and notable ability to invade and establish within multiple organs or the immunocompromised response of the host. Meanwhile, Centrocestus formosanus and Quadriacanthus aegyptiacus were exclusively detected in the gills, with an overall parasitic infection rate of 60 %. The present study is one of the few studies documenting Centrocestus sp. in catfish which reflects its ability to spread in new hosts and environments. A novel morphological dimension was recorded for the recovered metacercariae. The hematological, along with the identified lesions from light histological and TEM examinations in heavily infected catfish, indicate the detrimental impact of parasite infiltration on fish health status. Besides the biochemical biomarkers were significantly (p ≤ 0.05) affected by increasing the degree of infection. This study underscores the profound influence of parasitic infestations on the health of C. gariepinus, emphasizing the urgent need for effective management strategies in aquaculture to mitigate these effects, the spread of new pathogens, and ensure the sustainability and productivity of catfish farming. By integrating parasitological, morphological, histopathological, and biochemical analyses, this research provides valuable insights that contribute to better health management strategies in aquaculture and a deeper understanding of parasite biology.