TP53 is mutated in over half of all human cancers, making it the most important tumor suppressor. p53 sequence includes an N-terminal domain (NTD), a DNA binding domain (DBD), and others. NTD is an intrinsically disordered and interacts with many proteins, acting as a hub for cellular signaling. Using a combination of computational and experimental approaches including NMR, we show NTD have dynamic interactions with cyclophilin D (CypD), a mitochondria proline isomerase with key roles in cellular necrosis and mitochondrial energy metabolism. We show that a subset of p53 truncation mutations can promote cancer cell proliferation and mitochondrial metabolism in a CypD-dependent manner. Although dynamic interfaces are often considered “undruggable”, we have demonstrated that EGCG, the active ingredient of green tea, can bind to NTD and disrupt NTD-CypD interaction, inhibiting the effects of p53 truncation mutants. Our studies point to a novel mechanism for p53 gain-of-function (GOF) mutations through NTD interaction with mitochondrial CypD. Our data also provide novel insights into dynamic interactions of IDPs and small molecule engagement of such challenging drug targets, with important implications for cancer treatment and many other diseases.