Simple SummaryHigh ambient temperature provokes heat stress in animals. Observed signs of heat stress in pigs include altered physiological constants, changes in feeding behavior, reduced weight gain, or even body weight loss. Short-term exposition to heat stress has been associated with alterations in small intestine physiology, including digestion and absorption of nutrients. Those alterations reduce when pigs start the acclimation process to heat stress, which may occur at around one week of exposure to high ambient temperature. In this study, the short- (2 days) and long- (7 days) term exposure to natural heat stress on performance, blood components, and intestinal integrity of growing pigs were analyzed. Short-term heat stress reduced pig performance and altered blood components. Intestinal integrity was affected drastically at day 2 under heat stress conditions, but pigs started to recover most of their growth rate and intestinal integrity at day 7.The effect of short- and long-term exposure to heat stress (HS) was analyzed on blood components, performance, and intestinal epithelium integrity of pigs. Eighteen pigs (36.0 ± 3.5 kg BW) were assigned to three groups: thermo-neutral (TN); 2 d exposure to HS (2dHS); and 7 d exposure to HS (7dHS). Blood chemistry and hemogram analyses were performed; small intestine samples were analyzed for mRNA expression and histology. Compared to TN, 2dHS and 7dHS pigs reduced weight gain and feed intake; weight gain was higher in 7dHS than in 2dHS pigs (p < 0.05). White blood cells, platelet, and hematocrit were affected in 2dHS and 7dHS compared to TN pigs (p < 0.05). Short- and long-term exposure to HS affected blood concentration of triglycerides, urea, total protein, and albumin (p ≤ 0.05). Villi-height and crypt-depth decreased in HS pigs (p < 0.01). Mucin-producing and apoptotic cell number increased in 7dHS compared to TN pigs (p < 0.05). Expression of tight-junction-proteins decreased in 2dHS pigs compared to TN and 7dHS pigs (p < 0.05). Short-term exposure of pigs to HS dramatically affects performance, blood components, and integrity of the small intestine epithelia; nevertheless, pigs show signs of recovery at 7 d of HS exposure.