Cancers of the gastrointestinal tract constitute one of the most common cancer types worldwide and a ∼58% increase in the global number of cases has been estimated by IARC for the next twenty years. Recent advances in drug delivery technologies have attracted scientific interest for developing and utilizing efficient therapeutic systems. The present review focuses on the use of nanoscale MOFs (Nano-MOFs) as carriers for drug delivery and imaging purposes. In pursuit of significant improvements to current gastrointestinal cancer chemotherapy regimens, systems that allow multiple concomitant therapeutic options (polytherapy) and controlled release are highly desirable. In this sense, MOF-based nanotherapeutics represent a significant step towards achieving this goal. Here, the current state-of-the-art of interdisciplinary research and novel developments into MOF-based gastrointestinal cancer therapy are highlighted and reviewed.