As one of the most important tumor suppressors, the p53 protein regulates the expression of hundreds of target genes to orchestrate diverse cellular processes and safeguard genomic stability and integrity. While extensive studies have elucidated the structural features of p53 and the role of post-translational modifications in modulating its function, a comprehensive understanding of the dynamic behavior of p53 during activation and the precise mechanisms by which it regulates target gene expression remains lacking. In recent years, advances in single-cell imaging and spatiotemporal omics have provided new insights into the time-resolved regulation of p53. This review summarizes the multilayered architecture of the p53 regulatory network, spanning molecular modifications, subcellular localization, DNA binding, chromatin remodeling, and the expression dynamics of downstream target genes. We highlight how information is integrated and coordinated across these regulatory layers. Through dynamic signal decoding and finely tuned control mechanisms, p53 achieves precise regulation of cell fate decisions. A deeper understanding of p53 regulation is critical for elucidating the mechanisms of tumorigenesis and for developing targeted therapeutic strategies.