Replacing fishmeal with alternative protein sources and improving new ingredients diets with feed additives are major objectives in aquaculture. The aim of this study was to evaluate benefits for rainbow trout (Oncorhynchus mykiss) of supplementing a fishmeal-free diet, composed of processed animal proteins (dehydrated poultry protein, hydrolyzed feather meal, poultry and pork blood meal), with yeast extract. Juvenile rainbow trout (initial weight 37 ± 2 g) were fed either with a control diet (19% fishmeal) or with a diet based on terrestrial animal by-products (17%) supplemented or not with 3% of yeast extract. Effects of the diets were evaluated in a 4-week digestibility trial and a 12-week growth experiment. Fish health was investigated by measuring plasma immune markers and performing histological study of the gut. Underlying molecular responses were investigated using unbiased transcriptomic analysis of the liver and distal intestine. Results indicated that supplementing with 3% yeast extract did not influence nutrient digestibility substantially. Nevertheless, fish fed the yeast supplemented fishmeal-free diet grew more than those fed the non-supplemented processed animal protein diet (final body weight of 206.7±14.2g vs 182.3±13.5g) but less than their counterparts fed the fishmeal diet (230.5±7.6g). Plasma and structural parameters indicated no exacerbated immune response or signs of intestinal inflammation in fish fed the fishmeal-free diets. However, plasma total immunoglobulin M levels and intestinal villi were significantly higher in fish fed the diet supplemented with yeast extract. The transcriptomic analysis revealed that the diets influenced immune, inflammatory, pathogen fighting and coagulation gene-related expressions. These results suggest that the dietary inclusion of yeast can enhance a fishmeal-free diet by improving rainbow trout performances and potentially their robustness.