Oreochromis niloticus (genetically improved farmed tilapia, GIFT) often bites the root of Polygonum cuspidatum when it is used as a floating bed, and resveratrol (RES) is mainly accumulated in the root of P. cuspidatum. Blood acts as a pipeline for the fish immune system. Generating blood transcriptomic resources is crucial for understanding molecular mechanisms underlying blood immune responses. In this study, we determined the effects of RES administration on blood transcriptomic response in GIFT. With increasing RES concentration, 133 (0.025 vs. 0.05 g/kg RES), 155 (0.025 vs. 0.1 g/kg RES), and 123 (0.05 vs. 0.1 g/kg RES) genes were detected as significant differentially expressed genes (DEGs). Three and ninety-five shared significant DEGs were found to be enriched among the three (except 0.1 g/kg RES) and four groups (0, 0.025, 0.05, and 0.1 g/kg RES), respectively. To determine the relationship between mitochondrial regulation and RES supplementation, the results of RNA-Seq were analyzed and nine mitochondria-related genes (ATP synthase or mitochondrial-function-related genes) were verified. The results revealed the same expression pattern: cytochrome c isoform X2 (cox2), katanin p60 ATPase-containing subunit A1 isoform X1 (katna1), plasma membrane calcium-transporting ATPase 1-like (atp2b1) and GTP-binding protein A-like (gtpbpal) showed the highest expression in the 0.1 g/kg RES group, while NADH dehydrogenase [ubiquinone] iron-sulfur protein 2 mitochondrial (nad7), ATP synthase subunit beta, mitochondrial (atpb), ATP synthase subunit alpha, mitochondrial-like (atpal), ATP synthase subunit alpha, mitochondrial (atpa) and ATP-dependent Clp protease proteolytic subunit, mitochondrial (clpp) revealed a dose-dependent expression following RES supplementation. Blood Ca2+-ATPase activity, and malondialdehyde, glutathione, and ATP content were significantly increased in the 0.05 (except Ca2+-ATPase activity), 0.1 g/kg RES group when compared with the controls. Eighty-nine shared DGEs were mainly enriched in antigen processing and presentation, cell adhesion molecules and phagosome pathways, based on the comparison between previous reported hepatic and the present blood transcriptome. Our study demonstrated that RES supplementation might improve the resistance to metabolism dysfunction via mitochondrial energy synthesis and/or the respiratory chain (e.g., ATPase).