p53 protein is a well-known tumor suppressor factor that regulates cellular homeostasis. As it has several and key functions exerted, p53 is known as “the guardian of the genome” and either loss of function or gain of function mutations in the TP53 coding protein sequence are involved in cancer onset and progression. The Hippo pathway is a key regulator of developmental and regenerative physiological processes but if deregulated can induce cell transformation and cancer progression. The p53 and Hippo pathways exert a plethora of fine-tuned functions that can apparently be in contrast with each other. In this review, we propose that the p53 status can affect the Hippo pathway function by switching its outputs from tumor suppressor to oncogenic activities. In detail, we discuss: (a) the oncogenic role of the protein complex mutant p53/YAP; (b) TAZ oncogenic activation mediated by mutant p53; (c) the therapeutic potential of targeting mutant p53 to impair YAP and TAZ oncogenic functions in human cancers.