This study was conducted to investigate the effect of dietary porous ZnO supplementation on the growth performance, inflammatory cytokines and tight junction’s gene expression in weaned piglets. A total of 192 weaned piglets were randomly allocated to 4 experimental groups ( n =48/group) and fed, during 14 d, with one of the following dietary treatments: 1) basal diet (NC); 2) basal diet with 3,000 mg/kg of conventional ZnO (PC); 3) basal diet with 750 mg/kg of porous ZnO (low inclusion porous ZnO, LP-ZnO); 4) basal diet with 1,500 mg/kg porous ZnO (high inclusion porous ZnO, HP-ZnO). Results showed that dietary supplementation with regular ZnO or porous ZnO (750 and 1,500 mg/kg) improved average daily gain (ADG), feed to gain ratio (F/G) and jejunum morphology, while decreasing diarrhea incidence. Compared with the NC group, porous ZnO at both doses (750 or 1,500 mg/kg) increased serum alkaline phosphatase (ALP), immunoglobulin G (IgG) and insulin-like growth factor 1 (IGF-1) concentrations, but decreased serum glucose (GLU). Moreover, the mRNA expression of anti-inflammation cytokine (TGF-β), tight junction (Occludin, ZO-1) in the jejunum by different ZnO administration were significantly increased compared with the NC group, while mRNA expression of pro-inflammatory (IL-8), membrane channels that transport water (AQP3) and miR-122a were significantly decreased. It can be concluded that porous ZnO even at low dose (750 mg/kg) can be an effective alternative to pharmacological (3,000 mg/kg) conventional ZnO in reducing diarrhea, promoting the growth performance, increasing anti-inflammatory cytokines and tight junctions, reducing pro-inflammatory cytokines of weaned piglets.