The use of fish meal/oil in carnivorous fish feeds remains a concern for the environmental sustainability of aquaculture. In this study, we investigated the impact of an innovative diet designed to be cost-effective and environmentally sustainable (i.e., 60% replacement of fish meal by a blend of plant, yeast [Saccharomyces cerevisiae], and krill meal feed ingredients) on the growth, health, and welfare of gilthead seabream (Sparus aurata). Over a 135-day experiment, fish were fed either the innovative or a commercial diet (control), and various parameters were evaluated, namely growth performance, levels of physiological blood parameters related to stress, immunity, health, and welfare, as well as swimming activity, serving as a proxy for energy expenditure. Results revealed that the innovative diet enhanced growth compared to fish fed the control diet. Hematological and biochemical indicators did not highlight any impaired welfare condition in fish fed innovative diet while higher levels of Immunoglobulin M were measured in plasma of fish fed innovative diet, potentially suggesting enhancement of humoral immunity. However, accelerometer tags data revealed that fish fed the innovative diet exhibited higher overall swimming activity, suggesting higher energy expenditure, which was consistent with greater prealbumin levels measured in the plasma. In conclusion, the higher energy metabolism in fish fed the innovative diet might be compensated by the diet's content, which may boost humoral immunity and hence help the fish develop a better adaptation to rearing environment, including its viral and bacterial load, ensuring overall better growth. Longer term investigations, including measurements of additional parameters, are required to validate these promising preliminary outcomes.