Targeted protein degradation (TPD) represents a promising alternative to conventional occupancy-driven protein inhibition. Despite the existence of more than 600 E3 ligases in the human proteome, so far only a few have been utilized for TPD of histone deacetylases (HDACs), which represent important epigenetic anticancer drug targets. In this study, we disclose the first-in-class Fem-1 homologue B (FEM1B)-recruiting HDAC degraders. A set of 12 proteolysis targeting chimeras (PROTACs) was synthesized using a solid-phase supported parallel synthesis approach utilizing a covalent FEM1B ligand as an E3 ligase warhead. The evaluation of the HDAC degradation efficiency revealed substantial HDAC1 degradation by the top-performing degrader FF2049 (1g: Dmax = 85%; DC50 = 257 nM). Unlike our previously published cereblon-recruiting selective HDAC6 degrader, A6, which uses the same HDAC ligand, the FEM1B-based PROTACs achieved selective HDAC1-3 degradation. This unexpected change in the HDAC isoform degradation profile was accompanied by significant enhancement of the antiproliferative properties.