Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor involved in embryonic development, cell cycle regulation, autophagy, and DNA damage repair. Ferroptosis is a recently discovered form of cell death independent of apoptosis and is characterized by iron catalyzed lipid peroxidation. It has been hypothesized that Klf4 regulates ferroptosis-related genes. However, the molecular mechanism of how Klf4 regulates ferroptosis is yet unknown. In this study, mouse embryonic fibroblasts (MEFs) wild type for Klf4 (Klf4^+/+) or null for Klf4 (Klf4^-/-) were used to investigate the role of Klf4 in ferroptosis regulation. FIN56 is a drug that induces ferroptosis in cells via the degradation of GPX4, and thus reducing cellular protection against excess lipid peroxidation. MEFs both Klf4^+/+ and Klf4^-/- were treated with FIN56 to test the effect of Klf4 on sensitivity to FIN56 mediated cell death. In addition, trypan blue cell death assays were performed on MEFs untreated and treated with FIN56 to quantify the effects of the drug on cell death. Our findings revealed that Klf4^+/+ MEFs responded to FIN56 treatment with a significant increase in cell death, while Klf4^-/- MEFs showed resistance to the treatment. Furthermore, treatment of FIN56 with ferroptosis inhibitor (Fer-1) reduced Klf4^+/+ MEFs’ sensitivity to cell death, which further supports the hypothesis that Klf4 is positively regulating ferroptosis cell death. Finally, western blotting with primary antibodies for proteins involved in ferroptosis regulation revealed that Klf4^+/+ MEFs have higher levels of iron regulation proteins DMT1 and NCOA4, while the levels of iron storage protein FTH1 is reduced in response to FIN56 treatment. These results suggest that Klf4 is contributing to an increase of intracellular iron which could be sensitizing the MEFs to ferroptosis programmed cell death. Understanding this mechanism may illuminate possible targets for directed or combination therapy for cancer treatments.