Enterococcus faecalis is a newly emerged fish pathogen affecting many cultured fish species. The present work aimed to determine the cause of mortalities affecting the cultured Meagre farm and study the infectious agent virulence, disease pathology. Also, to determine the influence of infection on complement 3, cyclooxygenase, and lysozyme gene expression and concentrations in fish serum. The internal organs of diseased fish were severely congested with the presence of petechial haemorrhages on the liver, gonads, and all over the elementary tract. Thirty-one bacterial isolates were recovered from naturally infected fish; seventeen were identified biochemically as E. faecalis. Random E. faecalis isolate was verified for pathogenicity in meager fingerlings and was indeed pathogenic with lethal dose-fifty (LD50) estimated by 4.6 × 106 colony forming unit (CFU) fish−1. The posterior kidney and hepatopancreas of experimentally infected fish showed severe inflammation, necrosis, degeneration, and haemorrhage. Detachment of mucosa lining the stomach and intestine (intestinal villi and gastric glands) was prominent. The examined gastric tissues exhibited inflammation, leucocytic infiltration, and congestion. The expression of C3, Cox2, and Lyz was upregulated 24-h post-infection and then decreased near the baseline at 96 h. Serum C 3 and Lyz concentrations peaked at 24 h and 48 h after that decreased. IgM level gradually increased with time and peaked at 96 h. In conclusion, E. faecalis is assumed pathogenic for cultured meager, experimental infection stimulated immune systems and upregulated the expression of some immune-related genes.