Despite long non-coding RNAs (lncRNAs) emerging as key contributors to malignancies, their transcriptional regulation, tissue-type expression under different conditions, and functions remain largely unknown. Developing a combined computational and experimental framework, which integrates pan-cancer RNAi/CRISPR screens, and genomic, epigenetic, and expression profiles (including single-cell RNA sequencing), we report across multiple cancers, core p53-transcriptionally regulated lncRNAs, which were thought to be primarily cell/tissue-specific. These lncRNAs were consistently directly transactivated by p53 with different cellular stresses in multiple cell types and associated with pan-cancer cell survival/growth suppression and patient survival. Our prediction results were verified through independent validation datasets, our own patient cohort, and cancer cell experiments. Moreover, a top predictedp53-effectortumor-suppressivelncRNA (we termedPTSL) inhibited cell proliferation and colony formation by modulating the G2regulatory network, causing G2cell-cycle arrest. Therefore, our results elucidated previously unreported, high-confidence core p53-targeted lncRNAs that suppress tumorigenesis across cell types and stresses.Significance:Identification of pan-cancer suppressive lncRNAs transcriptionally regulated by p53 across different cellular stresses by integrating multilayered high-throughput molecular profiles. This study provides critical new insights into the p53 tumor suppressor by revealing the lncRNAs in the p53 cell-cycle regulatory network and their impact on cancer cell growth and patient survival.