Simple Summary Broiler chickens are frequently exposed to a variety of stress factors in the poultry industry. To simulate these factors, lipopolysaccharide (LPS) from E. coli is commonly used as a research model to stimulate inflammatory and oxidative stresses in broilers. LPS can reduce growth performance parameters by negatively affecting broilers' immune response to inflammation. Feed additives that could mitigate those detrimental effects are often demanded. The present study evaluated the impact of hydroxytyrosol supplementation on the growth performance, gut morphometry, and anti-inflammatory and antioxidant parameters of broilers challenged with LPS. Hydroxytyrosol improved the growth performance, gut morphometry, and oxidative status of broilers challenged with LPS. Therefore, hydroxytyrosol supplementation is a powerful nutritional intervention for mitigating the detrimental effects of LPS.Abstract This study assessed the effects of hydroxytyrosol (HT) on 8- to 20-day-old broilers challenged with lipopolysaccharide (LPS); 180 Cobb500 (TM) male chicks were randomly assigned to 3 treatment groups, each comprising 10 replicates with 6 birds per replicate. Treatments included a control diet (CON), CON with LPS administration, and CON + LPS supplemented with 10 mg of HT/kg of feed. LPS was administered intraperitoneally on days 14, 16, 18, and 20. Body weight (BW), body weight gain (BWG), and the feed conversion ratio (FCR) were measured. On day 20, ten birds per treatment were slaughtered for analysis. Bursa, spleen, and liver were collected, and their respective relative weight was determined. The jejunum was destined for morphological analyses of villus height (VH), crypt depth (CD), and their ratio (VH:CD), and for mRNA expression of nuclear factor kappa B (NF-kappa B), catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and interleukins 10 (IL-10), 1 beta (IL-1 beta), and 8 (IL-8). HT improved BW, BWG, and FCR, and reduced crypt depth (CD) while increasing the VH:CD ratio in the jejunum. Moreover, HT downregulated mRNA expression of CAT, GPx, IL-10, and IL-1 beta. In conclusion, HT enhances broiler growth performance, mitigates jejunal mucosa damage from LPS, and modulates antioxidant and immune responses.