Effects of a lipid-coated zinc oxide (ZnO) Shield Zn^® (SZ) vs. ZnO were evaluated. Forty 25-d-old weanling pigs were fed a nursery diet supplemented with 100 mg kg^-1 Zn with ZnO (ZnO-100), ZnO-2500, SZ-100, -200, or -400. All piglets were challenged orally with 5 × 10⁸ colony-forming units of enterotoxigenic Escherichia coli K88 on day 7 and euthanized on day 14. The fecal consistency score (FCS) was less for the SZ group vs. ZnO-100 (P < 0.05). The intestinal villus height:crypt depth ratio and goblet cell density were greater for the SZ group vs. ZnO-100. By regression analyses, SZ-100 to -200 and SZ-300 to -400 were comparable to ZnO-2500 in the FCS and intestinal variables, respectively. The jejunal mucosal mRNA level did not differ between the SZ group and either ZnO group in insulin-like growth factor-I and multiple structural proteins and cytokines including zonula occludens protein (ZO) 1 and interleukin (IL) 10 except for lower ZO-1 and IL-10 mRNA levels for the SZ group than for ZnO-2500 and ZnO-100, respectively. The ZO-1 mRNA level regressed positively on the supplemental SZ concentration. Results suggest that SZ play a role in epithelial barrier function and inflammation by modulating the expression of ZO-1 and IL-10.