INTRODUCTION: Over the past 20 years, the treatment landscape of HER2-amplified tumors has considerably evolved. Until now, no approved targeted therapies were available for patients with HER2-amplified metastatic colorectal cancer (mCRC). Tucatinib, a highly selective tyrosine kinase inhibitor, demonstrated significant efficacy in combination with trastuzumab in patients with refractory mCRC, leading to its approval by the Food and Drug Administration (FDA). AREAS COVERED: This review dives into the efficacy of tucatinib-based regimens in gastrointestinal malignancies, with a focus on the pivotal MOUNTAINEER trial, which led to the FDA approval of tucatinib plus trastuzumab in chemo-refractory HER2-amplified mCRC. Additionally, ongoing trials are exploring tucatinib in earlier treatment lines and across other gastrointestinal cancers, including biliary tract, gastric, and pancreatic malignancies. The mechanistic basis of dual HER2 inhibition and its implications for clinical practice are discussed. EXPERT COMMENTARY: The future of tucatinib-based therapeutic strategies in GI malignancies depends on their integration into different treatment lines. Addressing acquired resistance using liquid biopsy-guided strategies and other TKIs like lapatinib will be paramount to improve outcomes.