The topic of this research is to investigate the role of DEK on the p53 pathway under the influence of perfluooctanoic acid (PFOA), a persistent and commonly found “forever chemical”. Here the dose- and time-dependent toxicity of PFOA to DEK-knockdown and p53-knockdown HepG2 cells was observed and correlated to the expression level changes of p53, DEK, and MDM2 under siRNA transfection and PFOA treatments. Based on the results, a molecular mechanism was proposed in which cancer cells under the DNA damage inducing and thus p53 apoptosis pathway activating PFOA exposure, might protect themselves from death by upregulating the expression of DEK protein to facilitate DNA repair.