This study evaluated the effects of micro-encapsulated (protected) organic acids (OA) and essential oils (EO) combination, P(OA + EO), and effects of a regular blend of free acids (FA) on the growth, immune responses, intestinal barrier and microbiota of weaned piglets challenged with enterotoxigenic Escherichia coli (ETEC) F4 (K88+). A total of 30 crossbred (Duroc × Landrace × Large White) weaned barrows (7.41 ± 0.06 kg, 28 d old) were assigned randomly to 5 treatments: 1) non-challenged positive control (PC), 2) ETEC F4 (K88+)-challenged negative control (NC), 3) NC + kitasamycin at 50 mg/kg + olaquindox at 100 mg/kg + free acidifier (FA) at 5 g/kg, 4) NC + kitasamycin at 50 mg/kg + olaquindox at 100 mg/kg + P(OA + EO) at 1 g/kg (P1), 5) NC + kitasamycin at 50 mg/kg + olaquindox at 100 mg/kg + P(OA + EO) at 2 g/kg (P2). Each dietary treatment had 6 replicates of one piglet each and the study lasted for 3 wk. On d 7, pigs in NC, FA, P1 and P2 were orally dosed with 10 mL of ETEC F4 (K88+) culture (1 × 109 CFU/mL). From d 7 to 14 after the ETEC F4 (K88+) challenge, P1 increased gain-to-feed ratio (G:F) significantly (P