Despite the fact that 70% of the human genome is transcribed, only 2–3% of the human genome encodes transcripts which are translated into proteins [1], [2]. Recent approaches targeting genome-wide RNA sequencing in eukaryotes have revealed the abundance of noncoding RNAs (ncRNAs) which have diverse biological functions, transcription machineries, and mechanism of actions [3], [4]. RNA polymerase (RNA Pol) I and RNA Pol III-mediated transcription gives rise to most ncRNAs, including transfer and ribosomal RNA molecules [3], [5], [6]. Alternatively, RNA Pol II transcribes different types of small ncRNAs, such as microRNAs (miRNAs), small nucleolar RNAs (SnoRNAs), and piwi-interacting RNAs [2], [7], [8]. The longer RNA Pol II-transcribed ncRNAs, namely long non-coding RNAs (lncRNAs), are ncRNA transcripts that are >200 nucleotides in length [6], [9], [10], capped at their 5’-end, and commonly have a poly-adenylated tail at their 3’-end [5], [11], [12]. Remarkably, some lncRNAs have triple-helical RNase P-catalyzed structure at their 3’-end instead of the poly-adenylated tail, which functions in increasing the stability of the transcript [3], [13]. Compared to mRNAs, lncRNAs have shorter transcripts, contain fewer exons, and have shorter half-lives [14], [15]. The half-lives of lncRNAs are variable, but overall lncRNAs tend to be less stable than mRNAs [5], [16]. In addition, lncRNAs could function as an endogenous source for miRNAs synthesis or it influence miRNAs levels and functional activity through several sponging tactics at both the transcriptional and post-transcriptional stages [17]. There is an increasing interest in studying the role of lncRNAs in the development and progression of various metabolic diseases and cancers [6], [13], [15], [18], [19], [20]. Thus, this review aims at unraveling the role and mechanism of action of the lncRNA, maternally expressed gene 3 (MEG3), in the context of gastrointestinal (GIT) malignancies, and its potential as a therapeutic tool. Specifically, GIT malignancies associated with MEG3 include Gastric Cancer (GC), Colorectal Cancer (CRC), Hepatocellular Carcinoma (HCC), Pancreatic Cancer, Gall Bladder Cancer (GBC), Cholangiocarcinoma (CCA), Esophageal Cancer, and Gastrointestinal Stromal Tumors (GISTs). Notably, the review excludes Small Intestine Cancer and Anal Cancer due to the absence of investigations into their association with lncRNAs.