Aims The objective of this study was twofold: (i) to examine the effect of Clostridium butyricum on intestinal barrier function and (ii) to elucidate the mechanisms involved in enhanced intestinal barrier function. Methods and Results Forty‐eight weaned piglets were assigned randomly to either a basal diet or a C. butyricum‐supplemented diet. On day 15, all pigs were orally challenged with enterotoxigenic Escherichia coli (ETEC) K88 or saline. Clostridium butyricum decreased serum diamine oxidase activity and d‐lactic acid concentration, as well as increased intestinal tight junction proteins (ZO‐1, claudin‐3 and occludin) expression in ETEC K88‐infected pigs. Moreover, C. butyricum decreased IL‐1β and IL‐18 levels in serum and gut, whereas it increased IL‐10 levels. Furthermore, C. butyricum downregulated NLRP3 and caspase‐1 expression in ETEC K88‐challenged pig gut, but did not affect apoptosis‐associated speck‐like protein expression. Conclusions Clostridium butyricum enhanced intestinal barrier function and inhibited apoptosis‐associated speck‐like protein‐independent NLRP3 inflammasome signalling pathway in weaned piglets after ETEC K88 challenge. Significance and Impact of the Study The novelty of this study lies in the beneficial effects of C. butyricum on intestinal health, likely by improving intestinal barrier function and alleviating inflammatory reactions.