The cellular redox status has long been linked to different cellular functions, including protein quality control (PQC) and aging. The prominent molecular machine Cdc48 (p97/VCP in mammals) is one of the key players involved in PQC, shuttling misfolded proteins to degradation. Through a range of N-terminal interactions, Cdc48 recognizes ubiquitin-tagged proteins targeted for proteasomal degradation. Here, we show that yeast Cdc48 is a redox-switch protein, with oxidation of a thiol-switch in the conserved Cys115. Using redox mass spectrometry, we characterize the oxidation status of Cdc48’s cysteine residues in the shift from the early- to late-stationary stages. Cdc48’s interactome undergoes a proteomic-scale rearrangement following this oxidation and leads to an increased association with antioxidants. Moreover, we found that the oxidation status of Cys115 mediates the activity of Cdc48, its interaction with canonical cofactors such as Shp1, and subsequent involvement in maintaining protein homeostasis during chronological aging. This work not only points to a new thiol switch protein in the protein degradation pathway, but also defines new roles for Cdc48 in chronological aging.