After weaning, piglets suffer from various stresses, and their immune function declines, causing diarrhoea and death. In recent years, the intestinal health of piglets has been a hot topic in the field of swine nutrition and feedstuff research. The present work aimed to investigate the effects of Clostridium butyricum (C. butyricum) on plasma immune function, antioxidant activity and plasma metabolomics of weaned piglets. A total of 90 weaning piglets of average weight (6.22 ± 0.24 kg BW) and 28±2 days old were randomly divided into three groups: control diet, control diet + 0.1 g/kg antibiotic (colistin sulphate), and control diet + 5 × 108 CFU/kg C. butyricum. The pigs were divided into 6 pens per group with 5 piglets per pen for 21 days. Our results showed that the diet supplemented with 5 × 108 CFU/kg C. butyricum significantly reduced the levels of plasma glucose, total protein, high-density lipoprotein, phosphorus, IL-6, TNF-α, MDA and increased the levels of albumin, triglyceride, low-density lipoprotein, IgG, C3, SOD activity, T-AOC in the plasma (P