Gastrointestinal (GI) malignancies are notable for their high global health burden, bringing the toll of more than two million deaths every year and the evolution of the treatment paradigm. In this review, we discuss mRNA-based vaccines as an emerging treatment modality for both of these cancers and their transformative potential. We discuss the rapid development of mRNA as a platform technology, focusing on its unique versatility for customizable neoantigen targeting, its promising safety history, and its anticipated role in the field of immuno-oncology for the future. The review describes mRNA vaccines currently in development and discusses the overall landscape of clinical trials in GI cancers. We dissect significant learning in patient stratification, choice of trial design, and efficacy readouts by discussing completed and ongoing studies, including the positive results observed in pancreatic ductal adenocarcinoma. Although the potential is excellent, hurdles are also high. We discuss the immunological, technical, and logistical challenges, such as the immunosuppressive TME and the optimal delivery systems that currently prevent its wide clinical application. This review not only demonstrates the potential of mRNA vaccines to transform the treatment landscape in the field of GI cancers but also paves the way for future investigations, highlighting the importance of precision medicine in circumventing the challenges encountered to date and potentially changing the treatment platform altogether.