Ferroptosis is a form of iron-dependent, non-apoptotic cell death characterized by oxidative lipid peroxidation and iron accumulation. This review highlights the role of post-translational modifications (PTMs) and protein degradation in regulating ferroptosis. PTMs, including ubiquitination, phosphorylation, acetylation, O-GlcNAcylation, SUMOylation, methylation, N-myristoylation, palmitoylation, and oxidative modification, play crucial roles in modulating protein stability, activity, localization, and interactions, ultimately influencing iron and lipid peroxidation. Protein degradation pathways, such as the ubiquitin-proteasome system (UPS) and autophagy, are essential for maintaining appropriate protein levels and mitigating ferroptosis. The UPS is particularly important in regulating key regulators of ferroptosis, including iron metabolism, the GSH-GPX4 pathway, and the CoQ pathway. Autophagy, on the other hand, targets long-lived or aggregated proteins to prevent ferroptosis. The review also discusses the therapeutic implications of targeting PTMs and degradation pathways in diseases related to ferroptosis, providing new insights into potential therapeutic strategies for cancer and non-neoplastic diseases.Ferroptosis is a form of iron-dependent, non-apoptotic cell death characterized by oxidative lipid peroxidation and iron accumulation. This review highlights the role of post-translational modifications (PTMs) and protein degradation in regulating ferroptosis. PTMs, including ubiquitination, phosphorylation, acetylation, O-GlcNAcylation, SUMOylation, methylation, N-myristoylation, palmitoylation, and oxidative modification, play crucial roles in modulating protein stability, activity, localization, and interactions, ultimately influencing iron and lipid peroxidation. Protein degradation pathways, such as the ubiquitin-proteasome system (UPS) and autophagy, are essential for maintaining appropriate protein levels and mitigating ferroptosis. The UPS is particularly important in regulating key regulators of ferroptosis, including iron metabolism, the GSH-GPX4 pathway, and the CoQ pathway. Autophagy, on the other hand, targets long-lived or aggregated proteins to prevent ferroptosis. The review also discusses the therapeutic implications of targeting PTMs and degradation pathways in diseases related to ferroptosis, providing new insights into potential therapeutic strategies for cancer and non-neoplastic diseases.