The inclusion of insoluble NSP (iNSP) in weaner pig diets has been reported to decrease post-weaning colibacillosis (PWC). Conversely, soluble NSP (sNSP) have been shown to exacerbate PWC. The present study investigated the effect of NSP solubility and inclusion level on the health and performance of newly weaned pigs challenged with enterotoxigenic Escherichia coli (ETEC), using NSP sources known not to affect digesta viscosity, in a 2 x 2 x 2 factorial combination of NSP solubility (iNSP v. sNSP), inclusion level (low (L; 50 g/kg) v. high (H; 150 g/kg)) and ETEC challenge (infected v. sham). Infection had no effect on pig health, but reduced performance to a larger extent in pigs on the L diets compared with those on the H diets. The inclusion of sNSP significantly decreased the occurrence of diarrhoea (P < 0.001) and improved gut health, as indicated by a lower caecal digesta pH (P = 0.008) and increased (P = 0.002) Lactobacillus:coliform ratio, when compared with the iNSP diet on day 14 post-weaning. There was no effect of NSP solubility on ETEC shedding, digesta viscosity or pig performance. Pigs on the H diets had fewer cases of diarrhoea and shed fewer ETEC than those on the L diets. Increasing NSP inclusion significantly increased colonic Lactobacillus:coliform ratio, volatile fatty acid concentration and caecal digesta viscosity, but decreased performance. These results suggest that sNSP per se are not detrimental to pig health and that increasing the concentration of NSP in weaner diets that do not increase digesta viscosity may have a beneficial effect on gut health and protect against PWC.