Background: Antibiotic resistance and other adverse health issues related to the presence of drug residues in honey are of great concern to the United States, United Kingdom, and many other countries. The majority of quantitative testing methods using mass spectrometry are not capable of performing high-throughput analysis. Furthermore, the methods that are available are labor intensive and time consuming. Objective: There is a need for a rapid quantitative screening method to detect veterinary drug residues in honey for laboratories performing regulatory analysis. Herein is a method that utilizes automated solid-phase extraction that is directly coupled to a mass spectrometer for the screening of two macrolide drug residues, tylosin and erythromycin, in honey. Method: This method utilizes automated solid-phase extraction that is directly coupled to a triple quadrupole mass spectrometer for quantitative analysis. The optimized procedure requires minimal sample preparation, and can extract and analyze a sample on the mass spectrometer in approximately 20 s. Results: A complete method validation procedure was conducted to evaluate the effectiveness and robustness of this quantitative screening method. Quantitative results were within 15% of the target value, and no false positives or negatives were observed. Conclusions: The method validation illustrates that this is a viable screening method for regulatory analysis. Highlights: Complete automated extraction and analysis was performed, which involved minimal labor. Extraction and analytical times were reduced by >98% when compared with conventional methods. Furthermore, accurate quantitative results were generated on both fortified spikes and incurred honey residues.