Butyrate is a source of energy for colonic epithelia, anti-inflammatory and able to reinforce the intestinal defence barrier by producing mucins and hosting antimicrobial peptides, whereas tannins can exert antioxidant properties. However, , their combination has rarely been studied. A total of 216 weaning piglets (28 days old) were fed four diets for 35 days (nine pens with six piglets/diet) following a 2 x 2 factorial design. The two main factors were coated calcium butyrate (But) supplementation (0.15 % in diet) and tannins (Tan) (0.15 %). Pigs were fed a pre-starter diet (net energy (NE): 10.5 MJ/kg, DLys: 1.16 %) until day 14, followed by a starter diet (10.3 MJ NE/kg, DLys: 1.12 %). On day 13-14, two piglets from each pen were sampled for gut function and microbiome. From days 8 to 20, an episode of F4/F18+ E. coli infection occurred that caused severe diarrhoea; antibiotics were used, but mortality increased. While the percentage of piglets treated with antibiotics was 40.7 % for the control, it was reduced to 16 % for But, 27.8 % for Tan and 29.6 % when combined (P < 0.05). Interestingly, no mortality occurred for But, versus 14.8 % for the control, 5.6 % for Tan and 7.4 % when combined (P < 0.05). The main factors had no significant effect on performance criteria. However, their interaction had a significant effect, suggesting superior performance when feeding But alone (e.g., body weight on d35 of 19.9 kg versus the control of 17.9 kg, P < 0.05), while tannins, whether with (19.1 kg) or without (19.5 kg) But, did not. Faecal microbiota increased and diversified over time but was not influenced by treatment. In conclusion, But supported weaned piglets upon a health challenge and improved post-weaning performance, but the addition of tannins did not enhance these effects.