This study aimed to assess the effects of partial and complete replacement of synthetic vitamin E (Vit E) with grape pomace extract, rich in polyphenols, and wine lees derivatives, abundant in β-glucans, on broiler performance, meat quality, health biomarkers, and intestinal integrity. There was a control group (CON) fed a basal diet with commercially recommended Vit E levels, while a second group (GP) was fed the same basal diet included zin-bacitracin as an antimicrobial growth promoter. The remaining three groups (W25, W50, W100) had 25%, 50%, and 100% of Vit E replaced by 25, 50, and 100 mg polyphenols as GAE/kg feed from grape pomace extract, respectively, supplemented also with 150 mg β-glucans/kg feed. The W25 group tended to have lower body weight compared to the CON and GP groups (2565 g vs. 2762 g and 2727 g, respectively; p = 0.056), while feed intake was significantly higher in the CON group (p = 0.021). Malondialdehyde concentrations in breast and thigh muscles were elevated in the W100 group at 24– and 72–hours post-mortem (p = 0.039 and p = 0.030, respectively). Glutathione reductase levels in blood plasma were significantly reduced (p = 0.022) in the GP, W50, and W100 groups compared to CON. Additionally, CLDN1 expression in the jejunal mucosa was significantly increased in W100 compared to the CON group (p = 0.045). These findings suggest that partial substitution of Vit E with grape pomace and wine lees derivatives by 50% could be a feasible commercial dietary strategy since growth performance, oxidative status, and gene expression were not impaired. Created in BioRender.comHIGHLIGHTSComplete Vit E substitution increased lipid oxidation in breast and thigh muscles50% Vit E substitution with grape pomace and wine lees supports sustainable growthHigh polyphenol levels and wine lees increased CLDN1 expression in jejunal mucosa Complete Vit E substitution increased lipid oxidation in breast and thigh muscles 50% Vit E substitution with grape pomace and wine lees supports sustainable growth High polyphenol levels and wine lees increased CLDN1 expression in jejunal mucosa