Decades of selection for increased litter size has caused a proportion of sows to consistently produce low birth weight (LBW) litters resulting in economic loss for producers due to reduced piglet survivability and growth. We hypothesized that piglets from LBW litters would have altered gut microbial composition, intestinal architecture, and intestinal transcriptomic profiles compared with piglets from high birth weight (HBW) litters. Sows were designated LBW (n = 45) or HBW (n = 46) based on litter birth weights of three successive parities. LBW piglets were 22% lighter (P < 0.001) at birth; however, no longer differed (P > 0.05) in weight at weaning compared with HBW piglets. LBW piglets had reduced (P < 0.05) fecal microbial diversity with a 114% increase in fecal Enterobacteriaceae (P < 0.05), as well as reduced (P < 0.05) abundance of cecal Roseburia and Faecalibacterium, fiber-degrading butyrate producers. Several genes associated with metabolic (PER2, CES1, KLHL38, and HK2) and immune pathways (IL-1B, IRF8, and TNIP3) were differentially expressed, suggesting altered metabolic and immune function in LBW piglets. In conclusion, LBW piglets had potentially unfavorable shifts in microbial structure in comparison to HBW piglets accompanied with alterations in metabolic and immune gene expression. Results indicate some biological consequences linking LBW phenotype to changes in production efficiency later in life.