The involvement of noncoding RNAs (ncRNAs) in cancer pathogenesis has been increasingly appreciated. Although the expression and function of ncRNAs is highly tissue type- and context-dependent, we have found that long ncRNA (lncRNA) MILIP (Myc-inducible lncRNA inactivating p53) is commonly upregulated in TCGA cancer samples across 20 cancer types and that its high expression was associated with poor overall survival of patients. The increase in MILIP expression was subsequently corroborated using in situ hybridization (ISH) in a panel of colorectal cancer and a cohort of non-small cell lung carcinoma samples compared with paired normal tissues. shRNA silencing of MILIP reduced viability and clonogenicity in various types of malignant cells including A549 and H1299 lung cancer, MCF-7 and MDA-MB-231 breast cancer, U2OS and Saos-2 osteosarcoma and BE(2)C neuroblastoma cells, and retarded A549 and MCF-7 xenograft growth. Thus, MILIP functions as an oncogenic driver in diverse types of cancers. Strikingly, transcriptomics analysis revealed that the p53 pathway was mostly enriched in cells with MILIP silenced. Further mechanistic investigations demonstrated that MILIP was located to both the cytoplasm and nucleus, and that both fractions of MILIP contributed to its oncogenic role, as cytoplasmic MILIP accelerated p53 polyubiquitination and proteasomal degradation, whereas nuclear MILIP regulated p53 occupancy of its target promoters. Interestingly, we identified a consensus c-Myc binding site at the proximal promoter of the gene encoding MILIP that was transcriptionally activated upon binding to c-Myc. Indeed, MILIP upregulation appeared to be associated with MYC gene amplification. These results suggest that lncRNA MILIP plays a role in relaying oncogenic signaling of MYC to disabling the tumor suppressor p53. Of note, MILIP silencing also reduced viability of p53-null cancer cells and those carrying mutant p53, indicating that MILIP can also promote cancer pathogenesis independently of its effects on p53. Collectively, these findings identify MILIP as a pan-cancer associated oncogenic driver and implicate that MILIP may constitute a target for treatment of diverse types of cancer.