Host factors play essential roles in viral infection, and their interactions with viral proteins are necessary for establishing effective pathogenesis. p53 is a host factor that maintains genomic integrity by controlling cell‐cycle progression and cell survival. It is a well‐known tumor suppressor protein that gets activated by various stress signals, thereby regulating cellular pathways. The cellular outcomes from different stresses are tightly related to p53 dynamics, including its alterations at gene, mRNA, or protein levels. p53 also contributes to immune responses leading to the abolition of viral pathogens. In turn, the viruses have evolved strategies to subvert p53‐mediated host responses to improve their life cycle and pathogenesis. Some viruses attenuate wild‐type p53 (WT‐p53) function for successful pathogenesis, including degradation and sequestration of p53. In contrast, some others exploit the WT‐p53 function through regulation at the transcriptional/translational level to spread infection. One area in which the importance of such host factors is increasingly emerging is the positive‐strand RNA viruses that cause fatal viral infections. In this review, we provide insight into all the possible mechanisms of p53 modulation exploited by the positive‐strand RNA viruses to establish infection. This article is categorized under:RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional ImplicationsTranslation > RegulationRNA in Disease and Development > RNA in Disease The different strategies employed by positive‐strand RNA viruses to modify p53 during their course of infection.