<p>S-palmitoylation, a reversible lipid post-translational modification, plays a dynamically regulatory role in cell death signaling pathways by modulating protein-membrane affinity, subcellular localization, and functional interactions. Emerging evidence has linked dysregulated S-palmitoylation to various pathologies including cancer and neurodegenerative disorders. Recently, several advances highlight its novel involvement in ferroptosis, an iron-dependent programmed cell death mechanism characterized with lipid peroxidation and iron accumulation. However, the precise regulatory impact of S-palmitoylation on ferroptosis remains to be fully elucidated. Notably, certain key regulators of ferroptosis undergo degradation through autophagy pathways, indicating an intricate crosstalk between ferroptosis and autophagy. Herein, the current review summarized the molecular mechanisms and physiological functions of ferroptosis and S-palmitoylation, with a particular focus on the pivotal role of palmitoylated ferroptosis-related regulators. Importantly, the interaction between autophagy and ferroptosis, especially the S-palmitoylated proteins that modulate both processes were discussed as well. This review provides a new perspective for the accurate regulation of ferroptosis by modulating S-palmitoylation, thus may improve the overall prognosis through optimizing the treatment regimens or via enhancing the efficacy of existing therapies.</p>