The immediate post-weaning period is often associated with gut malfunction and diarrhoea for young pigs. Administration of antimicrobials remains an effective way to control weaning diarrhoea but it remains unclear how they affect gut physiology and microbiology although this is a prerequisite for being able to devise better alternatives. Hence, for 7 d we treated pigs, weaned at 24 d of age, with a combination of amoxicillin (25 mg/kg feed and injection of 8·75 mg/kg body weight per 12 h) and ZnO (2·5 g/kg feed). The pigs treated with antimicrobials (n 11) showed no signs of gut malfunction at any time, whereas untreated weaned controls (n 11) developed clinical diarrhoea. The antimicrobial treatment resulted in a higher daily weight gain compared with weaned controls (101 v. − 44 g/d, P < 0·0001), whereas both groups had a similar degree of villous atrophy compared with unweaned 24-d-old controls (n 8; P < 0·05). The antimicrobial treatment gave a dramatic reduction in small intestinal microbial diversity, and specifically prevented tissue colonization with Escherichia coli compared with weaned controls. Further, the antimicrobial treatment improved amylase, trypsin and small intestinal aminopeptidase A and N activities (all P < 0·05). Specifically for the colon, the antimicrobial treatment was associated with reduced tissue weight ( − 23 %, P < 0·05), reduced concentration of SCFA (P < 0·05), and increased mucosal goblet cell area (P < 0·0001) compared with weaned controls. We conclude that the beneficial effects of antimicrobials are mediated not only through reduction in intestinal bacterial load, but also through a stimulation of protein digestive function and goblet cell density.