The tumour suppressor p53 (encoded by TP53) protects the genome against cellular stress and is frequently mutated in cancer. Mutant p53 acquires gain-of-function oncogenic activities that are dependent on its enhanced stability. However, the mechanisms by which nuclear p53 is stabilized are poorly understood. Here, we demonstrate that the stability of stress-induced wild-type and mutant p53 is regulated by the type I phosphatidylinositol phosphate kinase (PIPKI-α (also known as PIP5K1A)) and its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Nuclear PIPKI-α binds to p53 upon stress, resulting in the production and association of PtdIns(4,5)P2 with p53. PtdIns(4,5)P2 binding promotes the interaction between p53 and the small heat shock proteins HSP27 (also known as HSPB1) and αB-crystallin (also known as HSPB5), which stabilize nuclear p53. Moreover, inhibition of PIPKI-α or PtdIns(4,5)P2 association results in p53 destabilization. Our results point to a previously unrecognized role of nuclear phosphoinositide signalling in regulating p53 stability and implicate this pathway as a promising therapeutic target in cancer.