Abstract The American swine industry relies on a model where facilities for farrowing are often geographically isolated from those used later for wean-finish, which necessitates multiple coincident stressors including weaning, mixing, transportation and feed/water restriction. Previous studies indicate this combined stress reduces subsequent growth performance; however, the specific impact of each stressor on an average, objectively healthy piglet is not well understood, nor is the acute physiological response to this life event. The objective of this study was to determine the effect these stressors on thyroid function, intestinal health, and body weight (BW) in average, healthy pigs. In this study, a total population of 588 piglets were weighed the day prior to weaning and 230 piglets with the lowest Z-scores for BW were selected (5.74 ± 0.70 kg). Piglets (n = 70) were weaned directly into nursery pens and provided with feed and water, 70 were transported for 10 h with no access to feed and water, and 70 were grouped together into 2 large pens with no access to feed and water for an equivalent 8 h period. The remaining 20 piglets were not weaned and served as an unstressed control group. A total of 10 pigs from each group were euthanized at 32 and 56 h post-weaning for tissue sampling. Ileal villi height, crypt depth, and goblet cell numbers were measured, and no treatment effects observed (P > 0.05). Serum triiodothyronine (T3) concentrations were measured pre-treatment (t = 0), 24 h (t = 24), 48 h (t = 48), and immediately following euthanasia (t = 32 or 56 d). There were no significant differences in serum T3 among treatments at t = 0. At all-time points post stress event, control piglets had greater T3 concentrations compared with feed restricted (P < 0.05) and transported (P < 0.05) pigs. Weaned pigs at t = 32, t = 48, and t = 56 had decreased T3 concentrations (P < 0.05) and weaned pigs tended (P = 0.0584) to have decreased t = 24 T3 concentrations compared with pigs remaining with the sow. The remaining pigs (n = 50) per weaning group were weighed weekly throughout the nursery phase and every 3 wk in the grow-finish phase to determine the impact of each stressor on growth. There was no significant effect of weaning treatment on BW at any time point (P > 0.10). Carcass data including carcass weight, loin and backfat depths, and lean percentage were measured at time of slaughter with no significant differences found among groups (P > 0.60). As no effect on growth weight or carcass characteristics were observed between treatment groups in average pigs, this suggests that it may be beneficial to transport average pigs the longest distance, while minimizing transport for pigs on either end of the weaning weight spectrum. Further research is needed to compare effects of weaning and transportation stressors on average and weight extremes of weaned pigs.