Under the condition of continuous administration, the present study investigated the metabolic residue of enrofloxacin and its metabolite ciprofloxacin in (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂), in order to provide theoretical basis for the scientific and reasonable use of enrofloxacin to prevent and treat the bacterial diseases of (E. fuscoguttatus ♀ × E. lanceolatus ♂), and to provide reference for the guidance of enrofloxacin usage in aquaculture. (E. fuscoguttatus ♀ × E. lanceolatus ♂) weighted (300±28) g were fed with 30 mg/(kg?bw) enrofloxacin by oral administration under the water temperature of 28℃, then the concentration of enrofloxacin and its metabolites ciprofloxacin in plasma, muscle and liver were determined by HPLC-MS. The results showed that enrofloxacin quickly reached the maximum in plasma, liver and muscle, while the peak time was 3 hours at the end of the fifth day, 3 hours at the end of the fifth day and 3 hours at the end of the fourth day, respectively. The concentrations were 24.5 mg/L, 13.0 mg/kg and 8.20 mg/kg, respectively. The peak time of ciprofloxacin in plasma, liver and muscle was 3 hours after the end of the fifth day, 3 hours after the end of the fifth day and 3 hours after the end of the fourth day, and the concentrations were 0.276 mg/L, 0.738 mg/kg and 0.110 mg/kg, respectively. Our results indicated that only a small amount of enrofloxacin was metabolized to ciprofloxacin, and it is suggested that the rest period should not be less than 980 degree-days.