The analysis of the dedifferentiation process has suggested that differentiated tumor cells undergo transformation toward cancer stem cells, accompanied by an increase in resistance to current chemotherapeutic treatments. Head and neck cancer (HNSCC) is a tumor with a high incidence and bad prognosis, and it is necessary to identify genes with alterations that can be explored therapeutically. PSMG2 is a chaperone protein that forms a heterodimer with PSMG1 and promotes the assembly of the 20S proteasome. Here, we characterized the effect of PSMG2 downregulation on tumorigenesis and the dedifferentiation process in head and neck cancer cell lines. We observed that high PSMG2 levels are associated with poor prognosis and survival in patients with HNSCC. Knockdown of PSMG2 reduced proliferation in vitro and in vivo in HNSCC cell lines. Moreover, the downregulation of PSMG2 diminished stemness, dedifferentiation and reprogramming properties. The reduction in PSMG2 levels caused the accumulation of polyubiquitinated proteins, increasing endoplasmic reticulum (ER) stress and activating apoptosis and autophagy as compensatory mechanisms. Furthermore, the response to proteasome inhibitors was increased in low-level PSMG2 patients. Therefore, PSMG2 is implicated in the assembly of the proteasome, which regulates ER stress as an essential cellular mechanism and autophagy and apoptosis as compensatory mechanisms for cellular homeostasis. PSMG2, and by extension the proteasome, is involved in cellular reprogramming and stemness.