Most eukaryotic proteins function as subunits within multimeric complexes. Imbalances in subunit levels disrupt assembly, leaving orphan proteins that are degraded by unclear quality control mechanisms. We identify the ubiquitin ligase HERC2 as a key regulator of this process. Proteomic analysis reveals HERC2 targets subunits from diverse complexes, including the proteasome, microtubule-associated structures, tRNA biosynthesis machinery, vesicle coats, centrosomes, Ski, and GATOR2. Focusing on the proteasome, we show that HERC2 mediates the ubiquitylation of at least eleven proteins involved in assembling the regulatory particle. Mechanistically, HERC2 recognizes unassembled subunits such as PSMC5, via interactions with chaperones like PAAF1, marking them for proteasomal degradation. Importantly, HERC2 deficiency disrupts proteasome activity in human cells, a defect also observed in patient-derived cells with HERC2-mediated neurodevelopmental disorders. These findings highlight the critical role of HERC2 in maintaining the assembly and activity of multimeric protein complexes.