This study aimed to conduct a multidisciplinary investigation integrating detailed morphology, molecular characterization, water parameters, histopathology alteration, and the trials of treatment of Clinostomum spp. In this study, 300 Nile tilapia (Oreochromis niloticus) were collected from the farmed and wild Nile River at Al Bahr Al Aazam, Giza Governorate to assess Clinostomid infection prevalence. Fish and water samples were collected from private fish farms, and water drains at Dakahlia, and Giza, Egypt. Analysis of the water revealed inadequate water quality, particularly in the fish farms. Snails and piscivorous birds were abundant at fish collection sites. The recovered Clinostomid MCs morphological characteristics and COI gene sequence analysis identified them as Clinostomum complanatum, C. phalacrocoracis, and Euclinostomum heterostomum. Clinostomid MCs disturbed the fish’s hematological and biochemical blood parameters. Bath treatment of parasitized fish with praziquantel (2 mg/L for 24 h) revealed a significant reduction in the number of vital MCs vs. infected fish (non-treated). Praziquantel (PZQ) is an effective and safe therapy for controlling Clinostomid infections affecting farmed Nile tilapia. The current findings indicate a link between poor environmental conditions and Clinostomum infections in tilapia. The study highlights the impacts of Clinostomid MCs on fish health and recommends bath treatment with PZQ as an efficient control method for these dangerous parasites to protect human and fish health.