Abstract: To monitor the safety of foods in terms of the restricted or banned compounds, it is especially preferable to develop generic methods which are capable of detecting as many different classes of concerned compounds as possible, with reliable confirm ability, satisfied sensitivity, good time-efficiency and high throughput. In this work, a method of ultra-high performance liquid chromatography (UPLC) quadrupole/exactive orbitrap mass spectrometry was developed for the rapid screening and semi-quantification of 200 drug residues in fish and shrimp. The sample was firstly added with 0.1 mol/L EDTA-Na₂, extracted with acetonitrile and ethyl acetate, cleaned-up by solid-phase extraction using Oasis PRiME HLB column. Then, the target compounds were separated on Thermo AccucoreaQ column (100 mm×2.1 mm×2.6 μm) with a mobile phase consisting of 0.1% formic acid and 0.1% formic acid-acetonitrile. The mass spectrometry data were acquired under Full MS/dd-MS² mode. Self-built database screening containing retention time, precursor ion and product ions were performed for qualification. The m/z of precursor ion, retention time (t_R) and fragment ions (FI) were acquired through analysis, while the isotope pattern for precursor was automatically calculated by TraceFinder software. And then, a database containing m/z of precursor ion, t_R, m/z of FI and isotope pattern were built in TraceFinder. Screening of all the analytes were performed by TraceFinder with the self-built database. The rules of screening were established as follow: allowed m/z deviation of precursor ion was 3×10^-6, allowed t_R deviation was ±15 s, at least one fragment ion match with allowed m/z deviation at 2×10^-5, and the fit threshold for precursor isotope pattern was 75% with allowed mass deviation at 10^-5, and allowed intensity deviation less than 25%. The full scan MS data was used for quantification, and the limits of detection was 1.50 μg/kg. The average spiked recoveries of 200 target compounds were 30%-120% with the relative standard derivations of 5%-30%, 70% of which were 5%-15%, and the higher relative standard deviations of 20%-30% were from samples with low spiked concentration. The developed method was successfully applied to the simultaneous determination of 200 drugs residues in fish and shrimp. The practical application showed that 9 compounds including ethoxyquin, enrofloxacin, ciprofloxacin, ofloxacin, norfloxacin, trimethoprim, sulfamethazine, dipterex, ivermectin were identified in 48 actual fish and shrimp samples. As a qualitative and semi-quantitative screening method, the features of simple pretreatment, simultaneous multiresidue detection, high efficiency and accuracy are demonstrated.