Compared to conventional soybean meal (SBM), processed soy protein has been demonstrated to have higher nutrient digestibility, leading to better animal growth performance and gut health. The aim of the present study was to test hypothesis that Provisoy, a SBM product produced via hydrothermal mechanical treatment could improve weaning piglet growth performance via higher crude protein (CP) digestibility compared to SBM and this benefit would be greater in pigs under Escherichia coli (ETEC) challenged conditions. A total of 268 weaned pigs (initial body weight, BW = 6.82 ± 0.85 kg) were allotted to a split plot design and pigs were housed in either a regular nursery condition (5 pigs/pen, 10-11 pens/treatment) or an ETEC challenged condition (3 pigs/pen, 12 pens/treatment, 1 pig per pen was orally gavaged with 10 mL O149K91K88 on d5 post-weaning). All pigs were fed one of the following diets: SBM, Provisoy or HP300. A standard wheat-barley-SBM based nursery diet was used and test soy products were added to replace SBM in the treatment diets. All diets were formulated to be isocaloric and had similar standardized ileal digestible lysine level in a three-phase (38 days) nursery program. One pig per pen was euthanized for ileal digesta and fecal samples were collected on post-weaning day 13 and 14. Data were analyzed by general linear model in R. In summary, there was no interaction between challenge condition and dietary protein source on intake and gain throughout all three phases. A significant interaction in G:F between d0-7 post-weaning (P < 0.05) was observed. As expected, pigs performed better in regular conditions compared to challenged conditions (P < 0.05). Dietary protein source significantly affected ADG (P < 0.05) and BW (P < 0.01) on post-weaning d7 regardless of challenge condition, with pigs fed Provisoy exhibiting increased ADG and d7 BW vs the control but not different than HP300. Similar improvement in growth performance was observed during d7-12 post-weaning. However, the effect of protein source on piglet growth was no longer evident during the last phase of nursery. There was no interaction observed between challenge condition and protein source on CP apparent ileal digestibility (AID) or apparent total tract digestibility (ATTD). Dietary protein source affected CP ATTD (P < 0.01), with Provisoy treatment having the highest value compared to other treatments. Challenge conditions tended to decrease CP AID (P = 0.109).