Diets with moderate levels of nonstructural carbohydrates (NSCs) elevate plasma lipopolysaccharide (LPS) at 2 hours and interleukin-1β (IL1B) at 1 hour postprandially. It is possible that rapid fermentation of NSC in the digestive tract lowers the pH, inducing inflammation. DigestaWell buffer, a bicarbonate-containing dietary supplement, may mitigate changes in LPS and IL1B through pH buffering. Six mature geldings, in a crossover design, consumed a feed providing 1.2 g/kg bodyweight of NSC. Plasma glucose, insulin, LPS, IL1B, and d-lactate were analyzed from samples obtained at −0.5, 1, 2, 4, 6, and 8 hours postfeeding. Whole blood was analyzed for pH and TCO2. Plasma glucose and insulin increased postprandially (P < .001); however, insulin responses were lower in horses receiving buffer (P = .017). The buffer also reduced plasma concentrations of IL1B (P = .039) compared to controls. Concentrations of d-lactate (P = .022) and LPS (P = .004) were affected by the time by treatment interaction, whereby control horses had higher concentrations of d-lactate at 2, 4, and 8 hours (P < .02) and LPS at 2, 4, 6, and 8 hours (P < .05). Meal consumption reduced blood pH (P = .011); however, pH was higher in horses receiving buffer (P = .012). Blood TCO2 levels remained <37 mmol/L but tended to be higher in horse receiving buffer (P = .081). Given these findings, we believe that DigestaWell buffer mitigates the negative effects of rapid NSC fermentation in the equine digestive tract, evidenced by reduced postprandial LPS and IL1B.