In real-world application, Cu/SSZ-13 simultaneously suffers severe deactivation from hydrothermal aging and SO2 poisoning during the periodic regeneration of diesel particulate filter (DPF). Herein, we first investigated the synergistic deactivation mechanism of hydrothermal aging and SO2 poisoning on Cu/SSZ-13 under SCR condition. Hydrothermal aging alone induces more severe degradation of selective catalytic reduction (SCR) performance than SO2 poisoning alone, while the presence of SO2 during hydrothermal aging causes further worse SCR performance compared with hydrothermal aging alone. Hydrothermal aging not only damages Si-OH-Al sites, particularly in four-membered ring (4MR) of the CHA cage, but also brings the conversion of ZCuOH, leading to the formation of inactive CuO/CuAlOx species. By contrast, SO2 poisoning alone is more prone to promote the transformation of ZCuOH to Z2Cu. Synergistic deactivation of hydrothermal aging and SO2 poisoning would exacerbate the damage of Si-OH-Al sites and then the formation of CuO/CuAlOx species. These results are expected to assist the knowledge-based catalyst design for diesel aftertreatment applications.