Gastrointestinal (GI) malignancies remain to be one of the most prevalent malignancies that are often characterized by a dismal prognosis. Nanoplatforms present a groundbreaking avenue for enhancing targeting strategies and multifunctionality in cancer treatment. The emergence of nanotechnology, particularly the innovation of smart responsive nanomaterials, has revolutionized cancer diagnosis and therapy. This review begins by exploring the design principles of smart responsive nanomaterials, focusing on the various exogenous and endogenous stimuli that drive their functionality. Furthermore, we provide a comprehensive summary of the applications of smart responsive nanomaterials in the treatment of GI malignancies over the past five years. Our aim is to contribute to the growing body of knowledge on smart responsive nanomaterials in GI malignancies, spark innovative ideas, and encourage further advancements in this field. Finally, we discuss the prospects and challenges associated with the use of smart responsive nanomaterials in GI malignancies.