The present study investigated the water quality index (WQI) of the Kshipra river at Dewas, Madhya Pradesh, India, using native fish Labeo rohita, and plant Eichhornia crassipes. The temperature, pH, dissolved oxygen, alkalinity, turbidity, and dissolved solids were found to be within the prescribed limits. However, heavy metals concentration exceeded the limit except for Cu and Zn. Their occurrence in river water was as follows: Ni > Fe > Cd > Cr > Mn > Zn > Cu. Among these heavy metals, Cd was found to be highly bioavailable, whereas Zn was the least bioavailable metal. Based on WQI, the water was found to be unfit for drinking, and the high WQI value was due to the presence of Cr and Cd. In fish tissues (muscle, liver, gut, gills, and kidney), the highest and lowest metal pollution index was found in gills (45.03) and kidneys (12.21), respectively. Bioaccumulation of these metals resulted in significant depletion of energy reserves (protein, glucose, and glycogen) and also altered hematological parameters. Moreover, liver function tests showed hepatic damage in the exposed fish. In-plant, both the bioaccumulation and mobility factor exceeded 1 for all these metals. On the other hand, the translocation factor was found to be beyond 1 for Fe, Ni, and Zn. These high values make this plant fit for phytoextraction of Mn, Fe, Cu, Zn, and Cd and phytostabilization of Cr in water. Moreover, consumption of L. rohita from the Kshipra River does not pose a non-cancer risk as the target hazard quotient was below 1, but it may pose cancer risk because of the presence of Cr in the range of 1.402 × 10−3 to 1.599 × 10−3.