The effects of active dry yeast, Saccharomyces cerevisiae boulardii (Scb), on the immune/cortisol response and subsequent mortality to Escherichia coli lipopolysaccharide (LPS) administration were evaluated in newly weaned piglets (26.1 ± 3.4 d of age). Barrows were assigned to 1 of 2 treatment groups: with (Scb; n = 15) and without (control; n = 15) the in-feed inclusion of Scb (200 g/t) for 16 d. On d 16, all piglets were dosed via indwelling jugular catheters with LPS (25 μg/kg of BW) at 0 h. Serial blood samples were collected at 30-min intervals from -1 to 6 h and then at 24 h. Differential blood cell populations were enumerated hourly from 0 to 6 h and at 24 h. Serum cortisol, IL-1β, IL-6, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) concentrations were determined via porcine-specific ELISA at all time points. In Scb-treated piglets, cumulative ADG increased (P < 0.05) by 39.9% and LPS-induced piglet mortality was reduced 20% compared with control piglets. White blood cells, lymphocytes, and neutrophils were increased (P < 0.05) in Scb-treated animals before LPS dosing compared with control piglets before being equally suppressed (P < 0.05) from baseline in both treatments after LPS dosing with a return to baseline by 24 h. Suppression of circulating cortisol concentrations (P < 0.05) was observed in Scb-treated piglets from -1 h to 1 h relative to LPS dosing compared with control animals before both peaked equally and subsequently returned to baseline. Peak production (P < 0.05) of IL-1β and IL-6 was less in Scb-treated piglets after LPS administration compared with controls before both equally returned to baseline. Peak TNF-α production in Scb-treated animals was accelerated 0.5 h and was greater (P < 0.05) than peak production in control piglets, after which both equally returned to baseline. The peak production of IFN-γ was greater and had increased (P < 0.05) amplitude persistence for 3 h in Scb-treated animals compared with control piglets before both equally returned to baseline. These results highlight the previously unidentified effects of Scb administration on immune and cortisol responses and the subsequent impact on growth and endotoxin-induced mortality in weaned piglets.