The main objective of the current trial was to evaluate the beneficial influences of Origanum vulgare leaf extract (OVLE) on growth, some blood indices, redox status, and the expression of some growth and immune-related genes. Three thousand seven hundred and eighty Nile tilapia fingerlings were allocated to six equal groups. The first group served as a control and received a basal diet, while the other five groups were fed diets containing graded amounts of OVLE (0.1, 0.2, 0.3, 0.4, and 0.5%, respectively) and defined as OVLE0.1, OVLE0.2, OVLE0.3, OVLE0.4, and OVLE0.5 for 98 days. Growth performance and feed efficiency parameters were significantly improved in OVLE0.4 and OVLE0.5 groups compared with the control group. The hematological indices, specifically hemoglobin, red blood cell, and white blood cell count were significantly increased in the fish group fed a 4% OVLE-supplemented diet compared to other groups. Fish fed higher dietary inclusion levels of OVLE significantly increased total protein and albumin concentrations compared to other experimental groups. The OVLE0.4 and OVLE0.5 supplemented groups promoted innate immune response and phagocytic activity and stimulated the lipase enzyme activity of Nile tilapia. All estimated redox markers were significantly improved in the fish groups that received 4 or 5% OVLE compared with the control and other OVLE groups. The fish groups fed higher levels of OVLE significantly upregulated the expression of GH, IL-8, and IL-1β genes and downregulated the expression of the Hsp70 gene. Furthermore, the intestinal histological features demonstrated normal structure in all OVLE-administered fish groups, with improved intestinal villus length compared to the untreated group. Finally, it could be concluded that including OVLE in the Nile tilapia diet at higher levels (0.4 up to 0.5%) could improve performance and general health status.