The gut-brain axis (GBA) is implicated in the development of obesity, and its role in developmental programming needs to be explored. This study uncovers the effects of a parental high-fat, high-sugar diet (HFS) on the gut (colon) and brain (hypothalamus) GBA of male Wistar rat offspring at weaning until adulthood. For ten weeks before mating, male progenitors were fed a control diet (CD) or HFS, whereas dams were fed CD or HFS during pregnancy and lactation. Male offspring aged 21-and 90-day old were assessed for: Gene expression of toll-like receptor 4 (TLR4) pathway and zonula occludens 1 (ZO1) in the colon and hypothalamus; hypothalamic gene expression of orexigenic neuropeptides and Leptin receptor; serum levels of lipopolysaccharide (LPS), glucagon like peptide 1 (GLP-1), Ghrelin and neuropeptide Y (NPY); colonic cytokine levels; FaecalBifidobacterium spp.andLactobacillus spp. DNA. Paternal HFS showed increased endotoxaemia, reduced colonic gene expression of ZO1 and reduced colonic TNF-α at weaning. In the adult offspring, paternal HFS showed increased NPY, reduced serum Ghrelin, colonic pro-inflammatory cytokines, and lower faecalBifidobacteriumspp. DNA. Maternal diet showed increased hypothalamic gene expression of myeloid differentiation primary response 88 (MYD88) at weaning. The maternal HFS diet showed increased NPY and reduced faecalBifidobacteriumspp. andLactobacillusspp. DNA in the adult offspring. The combined effect of parental diet showed increased NPY at weaning, and lowerBifidobacteriumspp. andLactobacillus spp.in the adult offspring. Maternal and paternal HFS diet seem to influence the programming of the gut-brain axis, leading to increased visceral adiposity and weight of male offspring at weaning, the effect that lasted until adulthood.