Activity-Based Probes (ABPs) have been used to dissect the biochemical/structural properties and cellular function of deubiquitinases (DUBs). However, their utility in studying cysteine-based E3 ubiquitin ligases has so far been limited. In this study, we evaluate the use of ubiquitin-ABPs and a novel set of E2~Ub-ABPs, on a panel of HECT E3 ubiquitin ligases. Our in vitro data show that ubiquitin-based ABPs can label HECT domains and we also provide the first evidence that, in addition to the RBR E3 ligase Parkin, E2-based ABPs can also label the catalytic HECT domain of NEDD4, UBE3C and HECTD1. Together, our findings provide novel insights into the use of ABPs for the study of HECT E3 ubiquitin ligases.