Enrofloxacin (ENR) is an antibiotic with rapid absorption and distribution, high blood concentration, long-term efficacy and high bioavailability, which has been widely used in preventing and treating of fish diseases. However, in recent years, the impact of ENR residues is a growing public concern on human and ecological safety. On the basis of studies on ENR elimination in fish, the structure and properties of ENR, the relationship between ENR and fish species, developmental stages, tissue differences, physiological and pathological conditions, dosages and modes of administration and environmental factors such as temperature, salinity, light, were reviewed, and the cause of formation of ENR residues in fish was analyzed retrospectively in this paper. For the first time, the hypothesis was firstly found and proposed that benthic fishes were more likely to form ENR residues than other water layer fishes, which probably was related to the ENR absorption by the organic matter in the sediment, and the photolysis of ENR could not be achieved in the dark sediment environment. It is suggested that the withdrawal period of ENR in bottom fishes should be redefined, and the mechanism of ENR residue in benthic fishes should be emphatically studied. It is proposed for the first time that the high dose ENR administration based on the selective mutation window theory is the main source of ENR residues in fish and environment.Therefore, in order to reduce ENR residue in cultured fish and environment, a reduction ENR dosing regimen was proposed on the basis of minimum inhibitory concentration of ENR, combining traditional Chinese herbal medicines with antibacterial and detoxification functions, to promote the elimination of ENR residues in fish, shorten the withdrawal period of ENR in fish, and reduce the risk of ENR resisting bacteria. At the same time, in order to reduce the environmental source of fish ENR, environmental ENR elimination techniques should be studied at the same time. This paper can provide new ideas for the scientific regimen of ENR and the risk control of ENR residues in cultured fish and environment.