Gastrointestinal (GI) cancers continue to be of significant concern to the public, amounting to 26% of all cancer diagnoses worldwide and 35% of all fatalities associated with cancer. The present-day treatment options for patients suffering from GI cancer including radiation therapy, chemotherapy, immunotherapy, and hormonal treatments have been the backbone of a patient’s recovery stage for several decades. Despite advancements in these treatment procedures, an effective cure for the permanent eradication of GI cancer is yet to exist. Researchers have now shifted their focus to the field of microRNAs (miRNAs), a class of small non-coding RNAs that have compelling evidence demonstrating their role in suppressing cancers, and they hope to develop miRNA modulators as a potentially useful weapon in the fight against GI cancers. In this chapter, the dysregulation of miRNAs in GI malignancies and a detailed study on the complex regulatory roles of miRNAs in the course of cancer are provided. It further delves into the therapeutic potential of miRNA modulators in arresting tumour growth, prospects of miRNA biomarkers, tumour-associated macrophages (TAM) polarisation, tumour microenvironments, and apoptosis of tumour cells. Moreover, this chapter also offers an insight into the progress of designing the miRNA modulators, the obstacles faced so far, and future perspectives in the use of miRNA as potent treatments for GI malignancies.