The large intestine epithelium plays an important role in water absorption and participates in fluid, acid-base and electrolyte balance, and the removal of waste products. The large intestine is rich in microorganism-presented enzyme activity. Apart from energy supply, the colon also participates in the synthesis of trophic factors and the modulation of the immune system and the systemic inflammatory response. The current study investigated the effects of dietary HMB administration to pregnant sows on the postnatal development of the colon in their offspring, at weaning. From the 70th to the 90th day of gestation, sows received either a basal diet (n = 12) or the basal diet supplemented with HMB (n = 12) at a dose of 0.2 g/kg of body weight/day. Maternal HMB treatment increased serum IgG and glucose concentrations and decreased serum urea concentration in the piglets. Basal histomorphometric analysis of offspring large intestines showed that prenatal HMB treatment led to a reduction in the thickness of the mucosa, submucosa and both types of myenterons, as well as reduced crypt thickness. The immunoreaction performed to mark T0 lymphocytes and total T lymphocytes in the colon wall showed that prenatal HMB treatment decreased the number of both types of lymphocytes. Greater expression for cadherin was found in the colon of piglets delivered by the HMB-treated sows. The expression of both tight junction proteins (occludin and claudin-3), as well as that of leptin, was stronger in the HMB-treated group. Vasoactive intestinal peptide (VIP) expression was stronger in the submucosal plexuses in the HMB maternal treated piglets, while no changes were observed in the myenteric plexuses. The results obtained indicate that the administration of HMB to pregnant sows significantly influenced the expression of leptin, VIP and some proteins of the intestinal barrier in their offspring, with less influence on large intestine basal morphology.