<p>Trifluridine/tipiracil (FTD/TPI) is effective for advanced colorectal and gastric cancers; however, limited real-world data exist on physician and patient experiences with non-hematologic toxicities such as nausea, anorexia, and fatigue. We investigated the real-world incidence and management of these side effects from both perspectives. A web-based questionnaire survey was conducted among physicians experienced in prescribing FTD/TPI and patients with colorectal or gastric cancer who were receiving or had received these medications. Patients reported non-hematologic toxicities‒fatigue, anorexia, nausea, diarrhea, and vomiting‒more frequently and earlier than physicians anticipated. Fatigue and anorexia were the most distressing side effects for patients and the most challenging for physicians to manage. Discrepancies existed between physicians and patients regarding communication and side-effect management strategies. Although nausea and vomiting were manageable with antiemetics, clear management methods for fatigue and anorexia have not been established. Patients valued detailed explanations about medication administration, non-hematologic side effects, and costs more than physicians recognized. In FTD/TPI therapy, a discrepancy exists between physicians’ and patients’ perceptions of non-hematologic toxicities, which may pose challenges in effective symptom management. Symptoms such as fatigue and anorexia appear to be less adequately addressed, highlighting the need for continued efforts to improve management strategies.</p>