Abstract: Antibiotic residues in milk powder are public focusing concerns relevant to food safety. Long-term exposure to antibiotic residues will lead to drug-resistant strains in human body, reduce body's immunity, and bring health hazards to consumers. Sulfonamides, (fluoro)quinolones and macrolides are high-frequency detecting antibiotic residues in matrix of milk powder. Rapid screening analysis of these residues and simultaneous confirmation with high confidence are valuable in practical scenarios of investigation testing, special monitoring program and so on. The direct analysis in real time (DART) ion source is an emerging technology of ambient pressure desorption ionization, it can directly complete the analysis of sample ionization and injection at the ambient pressure and open experimental environment, without changing the properties of the analyte itself. It became possible to analyze samples directly with minimal sample preparation steps or even without any sample pretreatment procedure with DART ion source. A hybrid high resolution mass spectrotmety, quadrupole-orbitrap high resolution mass spectrometry (Q-Orbitrap HRMS) is a powerful tool in veterinary drug residue analysis with superior specificity, accuracy and sensitivity. In present study, DART ion source was hyphenated to QOrbitrap HRMS to perform rapid screening analysis and simultaneously unambiguous identification of the above-mentioned antibiotic residues in milk powder. Sample was diluted in water and fast purified by filtering solid phase extraction column and then the filtrate was subjected to DART-Q-Orbitrap HRMS analysis. Several key parameters of the DART ion source, such as ionization type and temperature, as well as injection speed of DART ion source were optimized to enhance the performance of the method. Then, a QuickStrip (QS) Module was selected with the helium as carrier gas and ionization temperature as well as injection speed were set to 400 ℃ and 1 mm/s, respectively. The DART ion source with optimized settings coupled to Q-Orbitrap HRMS was finally applied to screening analysis. Results showed that 16 common-encountered antibiotic residues including sulfonamides, (fluoro)quinolones and macrolides can be effectively detected with the screening concentration of 100 μg/kg. Recoveries of the analytes ranged from 72.5% to 106.7% and the false negative rates were all less than 5%. Real-life sample analysis was finally conducted by the proposed method with an expected method performance, evidencing the potency of the developed method in risk monitoring in milk powder for veterinary drug screening analysis. It should be mentioned here that the screening concentration of 100 μg/kg is a compromised concentration for the sake of some less sensitive analytes to provide reliable determination of the antibiotic residues with the proposed procedures. It is, however, quite meaningful concentration to indicate the existence of high risk level of corresponding antibiotic residues which need to take actions. In total, the proposed method can play a role in risk monitoring laboratories and relevant industry institutions.