Transition from sow's milk to solid feed is associated with intestinal atrophy and diarrhea. We hypothesized that the intestinotrophic hormone glucagon-like peptide 2 (GLP-2) would induce a dose- and health status-dependent effect on gut adaptation. In Exp. 1, weaned pigs (average BW at weaning 4.98 ± 0.18 kg) were kept in a high-sanitary environment and injected with saline or short-acting GLP-2 (80 μg/(kg BW·12 h); n = 8). Under these conditions, there was no diarrhea and GLP-2 did not improve gastrointestinal structure or function. In Exp. 2, weaned pigs (average BW at weaning 6.68 ± 0.27 kg) were kept in a low-sanitary environment, leading to weaning diarrhea, and injected with saline or short-acting GLP-2 (200 µg/(kg BW·12 h); n = 11). Treatment with GLP-2 increased goblet cell density (P < 0.05) and reduced short chain fatty acid concentration in the colon (P < 0.01) but had limited effects on diarrhea. In Exp. 3, weaned pigs (average BW at weaning 6.90 ± 0.32 kg) were kept in a low-sanitary environment and injected with saline or a long-acting acylated GLP-2 analogue (25 µg/(kg BW·12 h); n = 8). In this experiment, GLP-2 increased intestinal weight (+22%; P < 0.01) and activity of brush border enzymes (+50-100%; P < 0.05). Circulating GLP-2 levels were in the pharmacological range in Exp. 3 (constant levels >20,000 pmol/L) and Exp. 2 (increases to 20,000 pmol/L for a few hours each day) while they were in the supraphysiological range in Exp. 1 (50-200 pmol/L). In conclusion, GLP-2 may improve gut structure and function in weanling pigs. However, the effects may be significant only under conditions of diarrhea and if GLP-2 exposure time is extended using long-acting analogues.