The p53 gene encodes a multi‐functional protein to prevent tumorigenesis. Although there have been many reports of the nuclear functions of p53, little is known about the cytosolic functions of p53. Here, we found that p53 is present in cytosol as well as nuclei under unstressed conditions and binds to clathrin heavy chain (CHC). CHC is known to play a role in receptor‐mediated endocytosis. Based on our findings, we examined the effect of p53 on clathrin‐mediated endocytosis of epidermal growth factor receptor (EGFR). Surprisingly, p53 co‐localized with CHC at the plasma membrane in response to EGF stimulation. In cells with ablated p53 expression by RNAi, EGFR internalization was delayed and intracellular signaling from EGFR was altered. Thus, our findings provide evidence that cytosolic p53 may participate in the regulation of clathrin‐mediated endocytosis to control the correct signaling from EGFR.