The employment of traditional bait and medicament in freshwater aquaculture causes the frequent occurrence of environmental pollution and disease. Effluent collected after Rhodopseudomonas capsulatus-mediated wastewater treatment could be re-utilized as microbial feeds, medicament, and aquaculture water to culture Tilapia mossambica. Therefore, a novel integrated system of wastewater treatment using effluent containing R. capsulatus that improves yield, increases disease resistance, and enhances the quality of aquaculture water for Tilapia mossambica culture was proposed and investigated. Tilapia mossambica can grow well in effluent containing R. capsulatus (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. capsulatus enhanced the activity of AICP, ACP, phagocytic, SOD and CAT by upregulating the expression of AKP, ACP, SOD and CAT genes. Theoretical analysis showed that biochemical molecules regulate the expression of these gene and enzyme activities by acting as a signal that stimulates the active center. Moreover, biochemical molecules present in R. capsulatus enhanced the activity of the mTOR and NF-kB signaling pathways. Furthermore, It capsulatus inhibited Aeromonas hydrophila that increases resistance against fish disease. Meanwhile, R. capsulatus 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 Tilapia mossarnbica, simultaneously.