The interplay between long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) is crucial in the epigenetic regulation of mRNA and protein expression, impacting the development and progression of a plethora of human diseases, such as cancer, cardiovascular disease, inflammatory-associated diseases, and viral infection. Among the many lncRNAs, growth arrest-specific 5 (GAS5) has garnered substantial attention for its evident role in the regulation of significant biological processes such as proliferation, differentiation, senescence, and apoptosis. Through miRNA-mediated signaling pathways, GAS5 modulates disease progression in a cell-type-specific manner, typically by influencing proteins involved in inflammation and cell death. While GAS5 is recognized as a tumor suppressor in cancer, recent reports highlight its broader regulatory capacity in non-cancerous diseases. Its modulation of protein expression through the GAS5/miRNA network has been shown to both mitigate and exacerbate disease, depending on the specific context. Furthermore, the therapeutic potential of GAS5 manipulation, via knockdown or overexpression, offers promising avenues for targeted interventions across human diseases. This review explores the dualistic impacts of the GAS5/miRNA network in conditions such as cancer, cardiovascular disease, viral infections, and inflammatory disorders. Through the evaluation of current evidence, we aim to provide insight into GAS5's biological functions and its implications for future research and therapeutic development.