Zinc oxide (ZnO) is currently used as a dietary supplement to support gut homeostasis during the standard 'abrupt' weaning practices in commercial pig production. However, a replacement is urgently required as a ban on ZnO usage is imminent. The objective of this study was to explore the potential of a bovine casein hydrolysate (5kDaR) and yeast β-glucan, and their combination, as an alternative to ZnO. Eighty 21d old male piglets received a basal diet or supplemented with 5kDaR and yeast β-glucan alone or in combination, or ZnO from the day of weaning and were monitored for 10 days (n = 8/group; dietary groups: control diet; control diet + 5kDaR; control diet + yeast β-glucan; control diet + 5kDaR + yeast β-glucan; control diet + ZnO). Individually, supplement yeast β-glucan or 5kDaR did not improve gut health. In contrast, the yeast β-glucan + 5kDaR combination supplement supported a healthy gut, indicated by healthy faecal scores and improved growth parameters; similar to ZnO inclusion (P > 0.05). There was no negative effect on the gut microbiota with yeast β-glucan + 5kDaR supplementation; while ZnO negatively affected the Bifidobacterium spp. abundance (P < 0.05). The inflammatory NFκB pathway was suppressed by yeast β-glucan + 5kDaR supplementation, similar to ZnO (P > 0.05). In conclusion, the dietary supplement yeast β-glucan + 5kDaR restored homeostasis of the newly weaned piglet gut similar to the widely used ZnO, and can potentially replace ZnO.