This study aims to evaluate the effects of dietary supplementation with Premna serratifolia or Punica granatum extracts on the immune response and disease resistance of striped catfish (Pangasianodon hypophthalmus). A basal diet was supplemented with 1.5% and 3% of P. granatum or 1% and 2% of P. serratifolia extracts (w/w) and fed to the fish. After 4 weeks of feeding, the numbers of erythrocytes and leukocytes (except for thrombocyte) were significantly higher in fish administered P. serratifolia extract compared to control. The serum lysozyme and complement activities were significantly higher in fish of 3% P. granatum, or 1%, 2% P. serratifolia extract treatments. All plant extract treatments showed significantly higher phagocytic activities compared to the control. Dietary inclusions of P. granatum and P. serratifolia up-regulated the expression of complement factor B/C2A and interleukin-1β gene in the liver of striped catfish. At the end of the feeding trial, the challenge test with Edwardsiella ictaluri showed that the cumulative mortality was lower in all extract supplemented treatments. In particular, the 2% P. serratifolia treatment showed the dramatically lowest mortality compared to others. In conclusion, dietary P. serratifolia and P. granatum extracts could stimulate the innate immune response of striped catfish and enhance disease resistance of fish against E. ictaluri.