A major function of the p53 tumor suppressor is the induction of a pleiotropic apoptotic program in response to stress through transcription‐dependent and ‐independent mechanisms. In particular, this includes a direct apoptotic role of p53 at the mitochondria. Stress‐induced p53 translocation to the mitochondria with subsequent outer membrane permeabilization is a common early component in p53‐mediated apoptosis in normal and transformed cells. However, the mechanism of p53 delivery to the mitochondria remains unknown. Here, we show that the cytoplasm contains a separate and distinct p53 pool that is the major source for p53 translocation to the mitochondria upon its stress‐induced stabilization. Using various manipulations that enhance or diminish p53 ubiquitylation, our data provide evidence that Mdm2‐mediated monoubiquitylation of p53 greatly promotes its mitochondrial translocation and thus its direct mitochondrial apoptosis. On the other hand, p53 does not require Mdm2 as a shuttler. Upon arrival at the mitochondria, our data suggest that p53 undergoes rapid deubiquitylation by mitochondrial HAUSP via a stress‐induced mitochondrial p53–HAUSP complex. This generates the apoptotically active non‐ubiquitylated p53. Taken together, we propose a novel model for mitochondrial p53 targeting, whereby a distinct cytoplasmic pool of stabilized monoubiquitylated p53, generated in resting cells by basal levels of Mdm2‐type ligases, is subject to a binary switch from a fate of inactivation via subsequent polyubiquitylation and degradation in unstressed cells, to a fate of activation via mitochondrial trafficking.