The aim of this study was to determine the effects of dietary inclusion of the combination of tributyrin with oregano or methyl salicylate as a substitute to antibiotics on gut health and microbiota of piglets. A total of 48 weaned crossbred piglets (Duroc × Large White × Landrace, 8.79 ± 0.97 kg, 21 ± 1 d) were randomly allocated to four experimental groups and fed for 4 weeks: the basal diet (Con); the control plus antibiotics (AB); the control plus oregano and tributyrin (OT); and the control plus methyl salicylate and tributyrin (MT). Although a numerical improvement on feed intake, weight gain and feed conversion ratio was observed in the OT and MT as well as the AB group, the difference was not significant (p > 0.05). The OT and MT groups were larger in villus height in the duodenum compared to the Con (p < 0.05), and were larger in relative abundance of Firmicutes/Bacaeroides in the intestine compared to Con and AB groups (p < 0.01). The amount of major different metabolites was 6, 8 and 8 for the AB, OT and MT groups when compared to the Con, respectively. In conclusion, as a substitute for antibiotics the inclusion of the combination of tributyrin with either oregano or methyl salicylate to the diet of weaned piglets improved the intestinal morphological structure and altered intestinal microbiota and metabolites, which were beneficial to the animal health.