The potential of a prebiotic oligosaccharide lactulose, a probiotic strain of Lactobacillus plantarum, or their synbiotic combination to control post-weaning colibacillosis in pigs were evaluated using an enterotoxigenic Escherichia coli (ETEC) K88 oral challenge. Seventy-two weanlings were fed four diets: a control diet (CTR), supplemented with L. plantarum (2 × 10(10) CFU ⋅ day(-1)) (LPN); with 10 g ⋅ kg(-1) lactulose (LAC) or a combination of both treatments (SYN). After 7 days the pigs were orally challenged. Six pigs per treatment were euthanized on days 6 and 10 post challenge (PC). Inclusion of lactulose improved the average daily gain (ADG) (P < 0.05), increased lactobacilli (P < 0.05) and the percentage of butyric acid (P < 0.02) in the colon. An increase in the ileum villous height (P < 0.05) and a reduction of the Pig Major Acute-phase Protein (Pig-MAP) in serum (P < 0.01) were observed also. The inclusion of the probiotic increased numbers of L. plantarum in the ileum and colon (P < 0.05) and in the total lactobacilli in the colon and trend to reduce diarrhoea (P = 0.09). The concentration of ammonia in ileal and colonic digesta was decreased (P < 0.05) and the villous height (P < 0.01) and ileal goblet cells (P < 0.05) increased at day 10 PC. A decrease in plasmatic TNF-α (P < 0.01) was also seen. Positive effects of both additives were combined in the SYN treatment resulting in a complementary synbiotic with potential to be used to control post-weaning colibacillosis.