Given the emergence of multidrug‐resistant bacteria, there is an urgent need for alternative methods to antimicrobials to prevent or treat piglet Post Weaning Diarrhoea (PWD). This study aimed to evaluate a potential interactions between a zinc oxide (ZnO) source formulation and a tannin mixture to improve performances of piglets in a model of enterotoxigenic Escherichia coli F4 (ETEC F4) infection. In total, 88 piglets (27.2
± 0.9 days of age; 7.3 ± 1.0 kg), genetically susceptible to ETEC F4, were randomly assigned to four groups. A tannin‐rich extract (TA) of chestnut and Quebracho (Silvafeed®Nutri P, Silvateam, Italy) was fed to the TA group (0.75% in feed). The nZnO group received a feed containing 150 ppm zinc from potentiated ZnO (HiZox®, Animine, France). The nZnO + TA group received a feed containing tannins and nZnO at the same doses as before. The C group received a standard feed formulated according to Swiss recommendations. Four days after weaning, piglets were infected with ETEC F4. Weight, daily intake per pen and faecal ETEC F4 levels were analysed with linear (mixed) effect models. Faecal scores were analysed with a cumulative link mixed model. Piglets with severe diarrhoea for five consecutive days were treated with antibiotics to ensure their welfare. Number of antibiotic treatments were compared with a fisher exact test. C group piglets had severe diarrhoea, and 18% had to be treated with antibiotics, compared to less than 4% in the other groups (P=0.05). Tannins and ZnO reduced faecal scores in the TA and nZnO + TA groups (P<0.005). Feed consumption in the TA and nZnO + TA groups was better than that in the C group (+0.05kg/d, P< 0.04). The addition of ZnO and tannins reduced the number of antibiotic treatments, but only tannins increased feed consumption and decreased diarrhoea severity.