The inclusion of fibre has been studied as an alternative to antimicrobials in weaning pig diets, while ZnO is used as an effective method to prevent post-weaning diarrhoea. However, it has not been investigated to what extent these two strategies interact with each other. The present study was designed to evaluate the effects of including wheat bran (WB) and ZnO alone or combined in the diet of early-weaning pigs on productive performance and microbial activity in the gastrointestinal tract (trial 1). A total of sixty-four piglets were distributed in a 2 × 2 factorial combination of two levels of WB (0 v. 40 g/kg) and ZnO (0 v. 3 g/kg) in the diet. The inclusion of ZnO in the diet improved the feed intake and growth of the animals and reduced the incidence of diarrhoea. The inclusion of WB increased SCFA concentrations and decreased Escherichia coli counts. However, simultaneous incorporation of WB and ZnO increased E. coli counts. Two in vitro trials were also designed to clarify hypotheses derived from the in vivo test: (1) the ability of WB and other fibre sources to bind E. coli in vitro (trial 2) and (2) the in vitro interactions between WB and ZnO with respect to E. coli growth (trial 3). We can conclude that incorporation of WB in the diet improved gut health by modulating the activity and composition of the microbial population. The negative interaction between WB and ZnO raises the interest of considering the inclusion of phytase enzymes to reduce the therapeutic levels of ZnO in post-weaning diets.