El-Temsah Lake is considered the largest water body in the Ismailia governorate, with a total area of 14 km². A total number of 120 moribund crabs (Callinectes sapidus) were collected from El-Temsah Lake in front of the youth house, Ismailia Governorate, in September 2021. The analyses of water parameters revealed high concentrations of un-ionized ammonia and nitrite. Clinically, moribund C. sapidus showed loss of escape reflex, lethargy, sluggishness, easily catching, and shell lesions on the dorsal cuticle, swimming legs, and walking legs. Several affected C. sapidus showed softening of the cuticle. Internally, the intestine is devoid of food, gills show blackening, and a straw yellow fluid is accumulated around the hepatopancreas. Enterococcus gallinarum was isolated from hemolymph, gills, and shell then identified by traditional bacterial methods, Vitek 2 system, and DNA sequence. C. sapidus was infected with E. gallinarum, with rates of 90% and 83.33%, respectively, in sites 1 (El-Taween club) and 2 (Beach club). E. gallinarum was sensitive for Ciprofloxacin and Rifampicin; whereas, it showed resistance to Vancomycin, Erythromycin, Chloramphenicol, and Tetracycline. It was obvious that the high mortality rate of C. sapidus was associated with deleterious water quality and E. gallinarum infection.