The effects of a functional additive (Sanacore® GM; SAN) on immune and antioxidant indices, and the resistance of gilthead seabream (Sparus aurata) against Vibrio alginolyticus infection were investigated. For this, four diets containing 0% (the control), 0.1%, 0.2%, and 0.4% SAN were offered to triplicated groups of fish (20–23 g) for ten weeks. Subsequently, fish were injected intraperitoneally with V. alginolyticus and monitored for further ten days. Feeding the fish on SAN-supplemented diets showed positive effects on leukocyte counts and its differential percentages. Serum lysozyme activity and total immunoglobulin values, as well as blood phagocytic activity and indices, were linearly and quadratically higher in SAN-fed fish, especially at the 0.4% SAN diet. Similarly, linear and quadratic increases in catalase, superoxide dismutase, and total antioxidant capacity were observed in SAN-fed fish, particularly at the 0.4% SAN diet. Conversely, malondialdehyde values decreased in SAN-fed fish compared with the control group, which showed its highest value. The highest expression of the IL-1β gene coupled with the lowest TNF-α and HSP70 genes expressions was found in the fish fed with the 0.4% SAN. On the other hand, fish fed on the control diet showed the lowest IL-1β gene coupled with the highest TNF-α and HSP70 genes expressions. After bacterial infection, most of the control fish died with a relative percent of survival of 5.0%; meanwhile feeding gilthead seabream on SAN-enriched diets significantly enhanced their protection against V. alginolyticus infection fed on the 0.4% SAN diet showed 100% survival. The SAN administration to gilthead seabream especially at the 0.4% level led to significant promotions in antioxidative and immune responses and augmented the fish resistance to V. alginolyticus infection.