A wide range of dietary phytochemicals have been demonstrated to improve the outcomes of thrombosis and stroke. Many of these compounds possess electrophilic functionalities that potentially engage in covalent bonding with the sulfhydryl side chain of cysteine residues within proteins. Despite this, the implications of such covalent modifications on platelet behavior and function have yet to be fully elucidated. To address this question, we assessed platelet phenotypes linked to the irreversible engagement of proteins by 23 electrophilic phytochemicals. This has led to identifying unique antiplatelet selectivity profiles for naturally-occurring isothiocyanates and polyphenols, whereby the response of platelets to ADP agonist was attenuated without impairing thrombin-mediated activation. By integrating a conventional Activity-Based Protein Profiling (ABPP) strategy, which utilizes alkyne-functionalized phytochemicals for target enrichment, with a multiplexed Tandem Mass Tag (TMT)-ABPP approach, we unveiled an unprecedented modulation of platelet ubiquitin signaling by specific dietary electrophiles. Further mechanistic profiling studies revealed how covalent modifications with these phytochemicals modulate novel E3 ligase and deubiquitinase activities, driving the ubiquitination of crucial signaling elements within the PI3K/Akt pathway to afford the unique antiplatelet phenotypes.