Footprinting mass spectrometry probes protein higher order structure (HOS) and dynamics by labeling amino acid sidechains or backbones as a function of solvent accessibility. One category uses residue-specific, irreversible covalent modifications, affording the user a flexible sample processing workflow for bottom-up analysis. Although several covalent labeling (CL) technologies are becoming established in structural proteomics, there remains a gap in the assessment of fundamental properties of established reagents and a set of criteria for their validation. Historically, CL reagents are applied to complex protein systems soon after their discovery and often without a thorough investigation of the intrinsic properties that affect their efficacy as footprinters. In this work, we developed a validation workflow to assess residue-specific modification, reaction “quench” efficacy, reagent-specific considerations (e.g., buffer pH), amino acid-specific kinetics compared to established reagents, protein-level reaction kinetics, ability to monitor changes in HOS in a two-state system, and label-induced protein HOS perturbation. With the workflow, we establish benzoyl fluoride (BF) as a next-generation CL reagent for modifying nucleophilic amino acid residues with applications envisioned in protein therapeutic discovery, development, and quality control. The high occurrence of hydroxyl-containing residues STY in paratope-epitope sites motivates the use of a highly reactive acyl-transfer reagent BF. To pursue this, we first probed reactivity of BF with STY-rich neuropeptide Y and observed high modification. To confirm modification specificity, we modified cyclic peptides with hydroxyl-, amine-, and thiol-containing side chains and locate the modification with MS². “Intrinsic” reactivity kinetics are monitored using the cyclic peptides and compared to those of an established nucleophile footprinter, diethyl pyrocarbonate (DEPC). Our BF footprinter demonstrates 10x greater reactivity with Tyr than DEPC. We also determine pH effects on reactivity and selecting a quench reagent. Finally, we demonstrate that BF can pinpoint the STY-rich binding site of biotin on streptavidin without perturbing HOS.