Microcystis aeruginosa, the dominant species causing cyanobacterial blooms, poses a serious threat to water environment security and development of aquaculture. The physiological stress in aquatic animals after exposure to M. aeruginosa has been extensively studied, however, the impacts on the physiological stress of aquatic animals in the process of controlling M. aeruginosa blooms remain unclear. In this study, we investigated the effect of quorum sensing autoinducer 2 (AI-2) on the algicidal activity of Deinococcus sp. Y35, and determined the effect of strain Y35 together with AI-2 on the physiological stress caused by M. aeruginosa to zebrafish. The results demonstrated that the synthesized AI-2 in vitro based on proteins MtnN and LuxS of strain Y35 could significantly promote the synthesis of algicidal pigment and improve the algicidal activity of strain Y35. The M. aeruginosa exposure could seriously damage the intestinal structure integrity of zebrafish, inducing oxidative stress and lipid peroxidation, as well as significant up-regulation of pro-inflammatory genes expression level. The separate application of strain Y35 could alleviate the physiological stress caused by M. aeruginosa including the protection of intestinal tissue, reducing oxidative stress and lipid peroxidation, as well as inhibition of pro-inflammatory genes expression. Meanwhile, the addition of synthesized AI-2 could significantly increase the alleviation effect of strain Y35 on the physiological stress. These results indicate that algicidal bacteria like Deinococcus sp. Y35 can play an important role in alleviating physiological stress of aquatic organisms and can be regarded as a potential resource for controlling cyanobacterial blooms and protecting aquatic organisms.