Hybridization is an effective way of improving germplasm in abalone, as it often generates benign traits in the hybrids. The hybrids of Haliotis discus hannai and H. gigantea have shown heterosis in terms of disease resistance than one or both parental species. In the present study, to elucidate the physiological and molecular mechanism of this heterosis, we analyzed the dynamic changes of several immune indexes including survival rate, total circulating haemocyte count (THC), phagocytic activity, reactive oxygen species level (ROS) and phenoloxidase activity (PO) in two parental species, H. discus hannai (DD) and H. gigantea (GG), and their reciprocal hybrids H. discus hannai ♀ × H. gigantea ♂ (DG), H. gigantea ♀ × H. discus hannai ♂ (GD) challenged with a mixture of Vibrio harveyi, V. alginolyticus and V. parahaemolyticus (which have been demonstrated to be pathogenic to abalone). Besides, we cloned and analyzed three important immune genes: heat shock protein 70 (hsp70), ferritin and cold shock domain protein (csdp) in H. discus hannai and H. gigantea, then further investigated their mRNA level changes in the four abalone genotypes after bacterial challenge. Results showed that these physiological and molecular parameters were significantly induced by bacterial exposure, and their changing patterns were obviously different between the four genotypes: (1) Survival rates of the two hybrids were higher than both parental species after bacterial exposure; (2) DG had higher THC than the other three genotypes; (3) Phagocytosis responded slower in the hybrids than in the parental species; (4) DD's ROS level was lower than the other three genotypes at 48 h post infection; (5) Phenoloxidase activity was lower in DD during the infection compared to the other genotypes; (6) mRNA levels of hsp70 and csdp, were always lower in at least one parental species (DD) than in the hybrids after the bacterial exposure. Results from this study indicate that the hybrids are more active or efficient in immune system function, hence they could effectively defense against a bacterial invasion, leading to higher survival rates after challenge. This study provides physiological and molecular evidences for interpreting the disease resistant heterosis in this abalone hybrid system, which could help us in a better understanding and utilization of heterosis in abalone aquaculture.