Excess use of antibiotics has led to antibiotic pollution in the environment, and now polluted sites have become hotspots for evolution and spread of antibiotic resistance in environmental bacteria. Subinhibitory concentration of antibiotics combined with other pollutant exerts selective pressure on environmental microbes, driving evolution and spreading antibiotic resistance. A mathematical model has been developed to have a better understanding of the subject of development of antibiotic resistance and its management in the aquatic environment. The model includes state variables such as fluoroquinolone, organic matter, heavy metals, resistant bacteria, and susceptible bacteria. The model was applied to the Musi River, which is heavily polluted with antibiotics. Simulations were carried out with hydraulic conditions and initial boundary conditions for state variables using actual site-specific data. Spatial pattern predicted by simulated results of the model is able to match with the observed spatial pattern of proliferation of resistance in the river. The developed model is also simulated for different pollution loading scenarios to predict and compare the future conditions for the river management. The simulated results showed that factors such as substrate concentration, antibiotic concentration, horizontal rate of transfer of plasmid, total population density of bacteria, and rate of losing plasmid dictate the dynamics of resistance in the river. © 2020 American Society of Civil Engineers.