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Simple Summary: This study evaluated the effect of dietary supplementation with organic silicon on the growth performance, blood biochemistry, digestive enzymes, morphohistology, intestinal microbiota and stress resistance in juvenile hybrid Tilapia (Oreochromis mossambicus × Oreochromis niloticus). It is concluded that organic silicon had no negative effects on the physiology and metabolism of the fish. The results showed that up to 50 mg·kg−1 of organic silicon can be applied to the diet of red Tilapia, improving digestive, metabolic and growth performance. The interactions between zootechnical performance, physiological digestive and metabolic capacity in hybrid red Tilapia still deserve further exploration. In recent decades, interest has been aroused worldwide in the use of silicon in nutrition; however, information on its effect on nutrition and metabolism of fish is limited. The objective of the research was to evaluate the effect of dietary supplementation with organic silicon on the growth performance, blood biochemistry, digestive enzymes, morphohistology and intestinal microbiota and stress resistance in hybrid Tilapia (Oreochromis mossambicus × Oreochromis niloticus). Methodologically, six levels of organic silicon (DOS) [control (0), 10, 20, 30, 40 and 50 mg·kg−1] were used to feed juvenile fish (initial weight 7.51 ± 0.25 g) grown for eight weeks in 18 aquariums (15 fish/aquarium). The results indicated that growth performance showed differences (p < 0.05) for specific growth rate, feed conversion and survival. Triglycerides, cholesterol and glucose, transaminases and digestive enzymes were significantly influenced by DOS levels. The histological study confirmed that the administered diets did not cause damage and induced significant morphological changes in the proximal intestine. The 16S rRNA gene sequencing analysis of the gut microbiota showed a high diversity and richness of OTU/Chao-1, with Fusobacteria, Proteobacteria, Bacteroidetes and Acidobacteria predominating in the DOS treatments compared to the control (p < 0.05). Induction of hypoxia stress after the feeding period showed a significant relative survival rate of 83.33% in fish fed 50 mg·kg−1. It is concluded that the DOS treatments performed better than the control treatment in most of the variables analysed. DOS had no negative effects on the fish. The results showed that up to 50 mg·kg−1 DOS improved digestive, metabolic and growth performance in hybrid Tilapia. [ABSTRACT FROM AUTHOR]