The employment of traditional bait and medicament in freshwater aquaculture causes the frequent occurrence of environmental pollution and disease. Effluent collected after Rubrivivax gelatinosus-mediated wastewater treatment could be re-utilized as microbial feeds, medicament, and aquaculture water to culture Crucian carp. Therefore, a novel integrated system of wastewater treatment using effluent containing R. gelatinosus that improves yield, increases disease resistance, and enhances the quality of aquaculture water for Crucian carp culture was proposed and investigated. Crucian carp can grow well in effluent containing R. gelatinosus (ER). The survival rate, yield, and whole body composition of the ER group were all increased compared to the control group (CK). The biochemical (B vitamin) and other substances in the effluent of R. gelatinosus enhanced the activity of proteases, amylases, lipases, AKP, ACP, phagocytic, SOD, CAT by up-regulating the expression of akp, acp, sod, and cat genes. Theoretical analysis showed that biochemicals regulate the expression of these gene and enzyme activities by acting as a signal that stimulates the active center. Moreover, R. gelatinosus and biochemical substances improved mTOR and NF-kB signaling pathway and intestinal microbiota. Furthermore, R. gelatinosus inhibited Aeromonas hydrophila that increases resistance against fish disease and promotes the growth of intestinal bacteria. Meanwhile, R. gelatinosus in the effluent also improved the aquaculture water quality. This technology would save the aquaculture water, reduce water pollution and wastewater discharge, and increase the output and disease resistance of Crucian carp, simultaneously. Copyright © 2019. Published by Elsevier Ltd.