Ferroptosis has become a promising target for cancer treatment since its discovery. However, tumor cells reinforce the defense systems to strengthen ferroptosis resistance. Here, we reported a positive feedback loop containing the serine and arginine rich splicing factor 6 (SRSF6) and fat mass and obesity-associated protein (FTO), which played crucial roles in the enhancement of cellular ferroptosis resistance and tumor progression in head and neck squamous cell carcinoma. Mechanistically, the SRSF6/FTO loop activated the sterol regulatory element binding transcription factors signaling pathway through FTO-mediated m6A demethylation, especially the upregulation of stearoyl-CoA desaturase, a key defender against ferroptosis. These findings provided new insights and directions for understanding the ferroptosis resistance of tumor cells.