Multiclass, multiresidue methods are becoming increasingly popular in regulatory monitoring programs due to their increased analytical scope and laboratory efficiency. In this work, we report the development and validation of a new high-throughput analytical method to monitor up to 131 veterinary drug residues, representing at least 13 different classes, in bovine muscle. This novel method streamlined sample preparation to <15 min/sample/analyst, or a batch of 40-60 pre-homogenized samples in <3 h/analyst, through the combination of dispersive solid-phase extraction with in-vial filtration (a new technique known as filter-vial d-SPE). The use of an enhanced sensitivity state-of-the-art tandem mass spectrometer led to <10 ng/g limits of quantification for nearly all drug analytes with injection of 0.17 mg of equivalent sample. Positive and negative switching in electrospray ionization was applied to cover all analytes in an 11-min liquid chromatographic separation. In the 3-day validation study, 100 of the drugs met quantification criteria of 70-120% recoveries and Horwitz Ratio ≤1.0, and the remaining analytes could still be screened at regulatory target levels. In the validation study involving >11,400 analyte results for spiked samples, the rate of false negatives for identification purposes was <5%, and no false positives occurred at appreciable concentrations.