Monopisthocotylean gyrodactylids and Edwardsiella tarda are potential piscine pathogens mainly associated with fish mortality and significant economic losses. In this study, a total of 100 African catfish, Clarias gariepinus were collected from an earthen ponds-based farm that experienced considerable mortalities with obvious septicaemic signs. The collected catfish were subjected to clinical, parasitological and microbiological investigations. Gyrodactylids were detected on the gill filaments of the examined fish specimens and were identified as Macrogyrodactylus spp. based on their morphological characteristics. The prevalence and intensity of Macrogyrodactylus spp. were 65% and 7.76 ± 0.20 / fish, respectively. On the other hand, E. tarda has been concurrently isolated from 70% of investigated catfish. E. tarda was phenotypically and molecularly characterized, and their antibiotic-resistant profile was investigated. The existence of pathogenic E. tarda in the same catfish infested with gyrodactylids probably augmented the clinical signs accompanied by the expansion of fish mortality. The experimental challenge with E. tarda proved that the current bacterial isolate was pathogenic to catfish based on the severity of the clinical signs and mortality rate. These findings suggested the existence of a possible synergism between E. tarda and Macrogyrodactylus spp. infections.