The present study evaluated the efficacy of dietary doses of Lactuca indica extract on immunological parameters and disease resistance against Streptococcus iniae infection in kelp grouper, Epinephelus bruneus. Fishes were fed with L. indica enriched diet at 1.0% and 2.0%; both the diets significantly enhanced NBT level and phagocytic activity on week 2 and 4 compared to control diet whereas the changes did not manifest on first week. The total immunoglobulin significantly enhanced in fish fed with 1.0% and 2.0% enriched diets whereas the lysozyme activity significantly enhanced all the diets from weeks 1 to 4. Further the enriched diets at 1% and 2% level resulted in lower mortality of 45% and 40% respectively indicating higher protection from S. iniae infection than 0.1% diet that resulted in 55% mortality. The results suggest that the dietary supplementation of L. indica extract stimulates the immunological parameters and increases disease resistance in E. bruneus against S. iniae infection.