| Summary: | Coccidiosis is a parasitic infection threatening poultry products globally. Parasite resistance to drugs is one of the barriers to <i>Eimeria</i> control. Natural products are one of the sources of compounds that prevent parasite infections. The current study was, therefore, conducted to evaluate the effect of <i>Vitis vinifera</i> leaf extract on anti-inflammatory response, oxidative status, and goblet cell response against <i>Eimeria papillate</i> infection in mice. Methanol was used as a solvent for phytochemicals. The mice were divided into six groups: The first group was the control. The second group was uninfected and treated with 200 mg/kg of extract to test toxicity, and the third, fourth, fifth, and sixth groups of mice received 1 × 10<sup>3</sup> sporulated <i>E. papillate</i> oocysts. The third group received no treatment. The fourth and fifth groups were treated daily with 100 and 200 mg/kg of <i>V. vinifera</i> leaf extract, respectively, while the sixth group received 25 mg/kg of toltrazuril daily via gavage. On day 5 p.i., the animals were sacrificed, and jejunum samples were prepared for analyses of histological sections and oxidative stress. The phytochemical analysis using GC-MS of the extract showed the presence of 12 biologically active compounds. The most effective dose was 200 mg/kg, which significantly decreased the number of parasitic stages in the jejunal sections of the mice. The findings demonstrate that <i>E. papillate</i> infection in mice results in significant histopathological changes in the jejunum, including inflammation, epithelial vacuolation, villi loss, and a decrease in goblet cell density. When infected mice received treatment, the histological injury score within the infected jejunum tissue decreased by 63%, and the goblet cell quantity dramatically increased, approaching the control values. Finally, the extract ameliorated the changes in glutathione and malondialdehyde due to <i>E. papillate</i> infection. The extract was proven to have anti-inflammatory properties and reduce the number of oocysts. Overall, the findings show that <i>V. vinifera</i> leaf extract has significant anticoccidial effects in vivo.
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