Interest in covalent drug discovery has surged in recent years, following the high-profile FDA approvals of covalent inhibitors that target BTK and KRAS G12C. High-throughput screening by intact protein mass spectrometry is a popular method for identifying lead matter from covalent fragment libraries. While the technique is proven in its capacity to confirm covalent binding, it does not provide binding site information on its own. Follow-up assays to identify binding sites can be time- and resource-intensive, potentially extending the hit confirmation timeline by weeks or months. Here, we describe the development of CoMPAS, a novel, targeted mass spectrometry-based covalent screening method that provides binding site information in the initial screen. The high sensitivity of targeted detection confers additional advantages over the intact protein method, including the ability to characterize more potent binders and reduced protein reagent requirements. Interpretation of the structure-activity relationship is simplified by enabling the use of binding site-specific EC50 values. To investigate higher-throughput screening beyond what is possible with standard liquid chromatography, we acquired data in parallel on an Agilent RapidFire system and compared the screening results by statistical analysis. To demonstrate the multiplexing capabilities of CoMPAS, we determined the target selectivity of screening hits against a pool of off-target kinases.