The posttranslational modification of histone proteins is a key mechanism in epigenetics. This mechanism includes the acetylation, methylation, phosphorylation, and other chemical modifications of the histone proteins. The acetylation is driven by histone acetyl transferases (HATs), while the deacetylation is catalyzed by histone deacetylases (HDACs). The latter has been under continuous investigation for drug discovery and beyond. So far, eleven zinc-dependent and seven NAD + -dependent HDAC enzymes have been identified, which are categorized in four classes. Class I consists of the isoforms HDAC1, 2, 3, and 8 and is mainly responsible for the cleavage of acetyl groups from histone lysine side chains. Inhibition of this class usually results in cytotoxic effects. Class II is further divided into two subclasses. Class IIa encompasses HDAC4, 5, 7, and 9, while class IIb includes HDAC6 and 10. Class III enzymes are the NAD + -dependent sirtuins and contain seven isoforms (Sirt1-7). Finally, class IV comprises only one enzyme, which is HDAC11. The FDA approval of four HDAC inhibitors as anticancer drugs (vorinostat, panobinostat, belinostat, and romidepsin) has shown the great potential of HDAC inhibitors in oncology drug development. The recent approval of givinostat for the treatment of Duchenne muscular dystrophy (DMD) highlights the expanding applications of HDAC inhibitors beyond oncology. In recent years, it has become evident that HDACs possess functions besides their traditional role in catalyzing the removal of acetyl or acyl residues. Consequently, targeted knock-down of these enzymes has the potential to profoundly affect disease-mediated cellular functions that are beyond the scope of traditional inhibition. One way to induce targeted degradation of HDACs is the development of HDAC proteolysis targeting chimeras (PROTACs). PROTACs are heterobifunctional molecules which consist of a ligand that binds to the protein of interest (POI), an E3 ligase ligand, and an appropriate spacer that connects the two binders. Through simultaneous binding to the E3 ligase and the POI proximity is induced and the E3 ligase is recruited to polyubiquitinylate the target which leads to its proteasomal degradation. In recent years, hydrazides have emerged as possible zinc-binding groups for HDAC inhibitors and degraders. Especially N-substituted hydrazides have gained attention in HDAC inhibitor and PROTAC development. Longer chain alkyl hydrazides have been shown to potently inhibit and degrade HDAC8, whereas n-propyl hydrazides have emerged as a class I selective zinc-binding group (ZBG). Ethyl hydrazides have also appeared and were shown to be a non-selective ZBG. But with fine-tuning of the cap group, this ZBG can also be employed to develop selective HDAC6 inhibitors. In this study, we aimed to develop HDAC6 degraders utilizing an ethyl hydrazide ZBG, as no published reports on ethyl hydrazide-based HDAC6 PROTACs are currently available.