Simple SummaryIn Mexico, the poultry industry uses antibiotics to improve meat production through increased feed conversion, growth rate promotion, and disease prevention. Nevertheless, due to the negative effects of antibiotic overuse and abuse, alternative strategies are required. Probiotics, Prebiotics, and Synbiotics are used as feed additives to maintain health and performance status in poultry production and have become a common method in preventing various gut diseases, but the mechanisms of how these mixtures promote animal health are still unclear. This work studies whether a Synbiotic, besides modulating the gut microbiota, can modify the intestinal mucosa ultrastructure, and if this modification can promote health conditions without affecting zootechnical parameters in broilers infected with Salmonella Typhimurium and Clostridium perfringens. Our results show that broilers treated with the Synbiotic, whether infected with pathogens or not, had healthier intestinal mucosa. The Synbiotic mix promotes structural changes in the intestinal mucosa, which in turn promotes the capacity to resist intestinal infections caused by S. Typhimurium and C. perfringens in broilers.Synbiotics can prevent gastrointestinal infections in broilers. This work studies the effect of a Synbiotic on broilers. One-day-old male broilers were divided into groups: Control; Synbiotic; Synbiotic + S. Typhimurium; Synbiotic + C. perfringens; Synbiotic + S. Typhimurium + C. perfringens; S. Typhimurium; C. perfringens; and S. Typhimurium + C. perfringens. Histopathological analysis revealed that the Synbiotic promoted longer villi, less deep crypts, and better villi-crypt ratio. Broilers treated with the Synbiotic, infected with pathogens or not, had healthier mucosa. In groups infected with pathogens, the frequency and intensity of histopathologic lesions were lessened often in groups treated with the Synbiotic. The Synbiotic group had higher lactic acid bacteria counts than the Control group on day 39, and the isolation frequency of S. Typhimurium was lower (p < 0.05) in the Synbiotic-treated groups. On day 18, mucosa, villi, villi-crypt ratio, crypt, and feed intake were influenced by Enterobacteriaceae. However, on day 39 (end of the trial), those parameters were influenced by lactic acid bacteria. The Synbiotic influenced morphological modifications in the duodenal mucosa, which in turn gave the broilers the ability to resist infections caused by S. Typhimurium and C. perfringens, by inhibiting their growth and decreasing the intensity and frequency of histopathological injuries.