Aquaculture is a fundamentally important sector of the global food supply, but it is also environmentally intensive. Conventionally used feed ingredients stand out among the factors that contribute to its high environmental footprint. For instance, fishmeal and fish oil rely on overexploited wild fisheries, while soybeans compete with human food resources. This study investigated how partially replacing fishmeal with the microalga Spirulina affects the morphophysiology and metabolism of Nile tilapia, one of the most widely farmed fish. In a previous study, we demonstrated that Spirulina improved the zootechnical performance of Nile tilapia. Here, we expand on those results by showing improvements in the fatty acid profiles and dietary fat quality of Spirulina-fed fish. Furthermore, proteomic analysis indicates a higher antioxidant capacity and more efficient lipid metabolism. Taken together, these results support the use of Spirulina as a fish feed ingredient to promote more sustainable aquaculture practices. Finally, this study provides a policy-based foundation for overcoming obstacles to implementing microalgae as an aquaculture feed ingredient.