A 9‐week feeding trial was conducted to evaluate the effects of replacing soybean meal (SBM) with sunflower meal (SM) or fermented sunflower meal (FSM) on the growth performance, intestinal microbiota, and intestinal health of genetically improved farmed tilapia (Oreochromis niloticus) (initial weight 6.55 ± 0.01 g). Eleven isonitrogenous and isolipidic experimental diets were formulated by replacing 0%, 20%, 40%, 60%, 80%, and 100% of dietary SBM with SM or FSM. The results showed that the replacement of more than 40% of SBM with SM decreased the weight gain and special growth rate of tilapia, while the complete replacement of SBM with FSM did not affect the growth performance of tilapia. From transmission electron microscopy analyses, it was shown that high levels of both SM and FSM substitution resulted in damage to the intestinal epithelium of tilapia. Replaced of 20% SBM with SM upregulated intestinal tight junction (zo-1, claudin, occludin) and anti‐inflammatory (tgf-β1, tgf-β2) gene expression and downregulated pro‐inflammatory gene expression (tnf-α, il-1β, il-6, il-8). However, the expression of tight junction, anti‐inflammatory, and pro‐inflammatory genes showed opposite trends when SBM was substituted by SM at high levels. FSM completely replaces SBM and downregulates the expression of tight junction genes (claudin, occludin), replacement of more than 20% of SBM with FSM downregulated pro‐inflammatory (tnf-α, il-1β, il-8) gene expression, whereas substitution of less than 80% increased the expression of anti‐inflammatory genes (tgf-β1). The 100% FSM group exhibited a decreased abundance of Fusobacteriota and an increased abundance of Actinobacteriota compared to the control and 100% SM groups. In summary, our data confirm that replacing more than 40% of SBM with SM induces gut inflammation, damages gut health, and decreases growth performance, whereas FSM replacement of SBM did not negatively affect tilapia growth and health, it also did not have a significant ameliorative effect, with some parameters negatively affected at high replacement levels. Therefore, FSM replacement of SBM levels above 80% is not recommended.