Swine dysentery, ileitis, and porcine salmonellosis are production-limiting diseases of global importance for swine production. They are caused by infection with Brachyspira hyodysenteriae, Lawsonia intracellularis, and Salmonella enterica serovar Typhimurium, respectively. Currently, the prevention, treatment, and control of these diseases still relies on antimicrobials. The goal of this study was to evaluate the effectiveness of four commercially available non-antimicrobial compounds in preventing lesions caused by the bacteria cited above using an in vitro intestinal culture model. A total of five pigs per pathogen were used and multiple compounds were evaluated. For compound F (a fungal fermented rye), S (a blend of short and medium chain fatty acids), and P (a synergistic blend of short and medium chain fatty acids, including coated butyrates), a total of four explants/pig for each treatment were used, while for compound D (an extract of carob and thyme) only 12 explants/pig for each treatment were used. Explants were exposed to a combination of pathogen only (n = 4/compound/pig), compound only (n = 4/compound/pig), or pathogen and compound (n = 4/compound/pig) and sampled at two time-points. Histopathology and gene expression levels were evaluated to investigate the treatment effect on explants. Short and medium-chain fatty acids, and an extract of carob and thyme, was found to mitigate lesions due to B. hyodysenteriae exposure. A fungal fermented prebiotic increased healthy epithelial coverage when explants were exposed to L. intracellularis or S. Typhimurium. These findings represent a step towards finding alternatives to antimicrobials usage and control of swine dysentery, ileitis, and salmonellosis in pork production.