Protein quality control systems and ER stress play critical roles in SARS-CoV-2-induced neurodegeneration. This review explores how SARS-CoV-2 exploits protein quality control systems, such as the Unfolded Protein Response (UPR), Endoplasmic Reticulum-Associated Degradation (ERAD), the Ubiquitin-Proteasome System (UPS), autophagy, and molecular chaperones, leading to proteostasis disruption and cell death. SARS-CoV-2 induces ER stress, which activates the UPR, but the virus manipulates these pathways to its advantage, contributing to neurodegeneration. ER stress and UPR activation are common in both neurodegenerative diseases and viral infections, suggesting a potential link between SARS-CoV-2 and neurodegeneration. The UPR involves three main pathways: IRE1, PERK, and ATF6, each with distinct roles in responding to ER stress. SARS-CoV-2 infection leads to ER stress and UPR activation, which can result in cell death and neurodegeneration. The ERAD and UPS systems are also involved in SARS-CoV-2 infection, with the virus manipulating these systems to facilitate replication and survival. Autophagy plays a dual role in SARS-CoV-2 infection, acting as both a defense mechanism and a target for viral manipulation. The interplay between autophagy and SARS-CoV-2 highlights the complexity of host-virus interactions and the potential for therapeutic interventions targeting these pathways. Understanding these mechanisms is crucial for developing strategies to combat SARS-CoV-2-induced neurodegeneration.Protein quality control systems and ER stress play critical roles in SARS-CoV-2-induced neurodegeneration. This review explores how SARS-CoV-2 exploits protein quality control systems, such as the Unfolded Protein Response (UPR), Endoplasmic Reticulum-Associated Degradation (ERAD), the Ubiquitin-Proteasome System (UPS), autophagy, and molecular chaperones, leading to proteostasis disruption and cell death. SARS-CoV-2 induces ER stress, which activates the UPR, but the virus manipulates these pathways to its advantage, contributing to neurodegeneration. ER stress and UPR activation are common in both neurodegenerative diseases and viral infections, suggesting a potential link between SARS-CoV-2 and neurodegeneration. The UPR involves three main pathways: IRE1, PERK, and ATF6, each with distinct roles in responding to ER stress. SARS-CoV-2 infection leads to ER stress and UPR activation, which can result in cell death and neurodegeneration. The ERAD and UPS systems are also involved in SARS-CoV-2 infection, with the virus manipulating these systems to facilitate replication and survival. Autophagy plays a dual role in SARS-CoV-2 infection, acting as both a defense mechanism and a target for viral manipulation. The interplay between autophagy and SARS-CoV-2 highlights the complexity of host-virus interactions and the potential for therapeutic interventions targeting these pathways. Understanding these mechanisms is crucial for developing strategies to combat SARS-CoV-2-induced neurodegeneration.