This study investigated the effects of a synbiotic Lacto Forte on growth performance, haemato-immunological responses, plasma bactericidal capacity, histological profiles and resistance of Oreochromis niloticus to Pseudomonas fluorescens. The experimental fish were divided into three groups; two of them (T1 and T2) were given Lacto Forte incorporated diets at increasing level (0.7 and 1.5 g/kg, respectively) and an additive-free basal diet served as the control (T0) for 30 and 45 days. At the end of the feeding trial, a challenge was performed using a virulent strain of P. fluorescens and mortalities were recorded over an additional 14-days period. The results showed that Lacto Forte has a pronounced effect on haematological and growth performance parameters at 1.5 g/kg rather than 0.5 g/kg (p < 0.05). Plasma lysozyme, proteases, antiproteases and bactericidal capacity were significantly enhanced (p < 0.05) in Lacto Forte-treated groups, particularly after 45 days of supplementation. Long-term supplementation with Lacto Forte (1.5 g/kg) induced degenerative changes in the liver, spleen and intestine. Additionally, a significant increase (p < 0.05) in survival rates were found in Lacto Forte-treated groups compared to the control one 14 days post-challenge. As a result, Lacto Forte fortifies tilapia immune response and can be used as a surrogate for antibiotics to control P. fluorescens. K E Y W O R D S bactericidal, growth performance, Innate immunity, Oreochromis niloticus, Pseudomonas fluorescens, synbiotic Lacto Forte How to cite this article: Ismail M, Wahdan A, Yusuf MS, Metwally E, Mabrok M. Effect of dietary supplementation with a synbiotic (Lacto Forte) on growth performance, haematological and histological profiles, the innate immune response and resistance to bacterial disease in Oreochromis niloticus. Aquac Res. 2019;50:2545-2562.