Objective: This study aimed to explore the efficacy and safety of Qingxin Fupi Jieyu formula (the herbal formula has the function of clear away the heart fire, tonify spleen, and relieve depression, QXFPJYF) in treating digestive tract cancer-related cognitive impairment (CRCI). Methods: 28 subjects with digestive tract CRCI were treated with QXFPJYF for 6 weeks. The scores of Montreal Cognitive Assessment and Mini-Mental State Examination were observed at four-time points (baseline, week 2, week 4, week 6). Besides, anxiety and depression scores and tumor markers were measured. Results: The scores of Montreal Cognitive Assessment and various fields were elevated steadily after treatment, such as visuospatial/executive, attention, language, delayed recall, and orientation. The differences were statistically significant (P < 0.05) besides the language score. The scores of Mini-Mental State Examination and various factors were elevated gradually at week 2, week 4 and week 6, including language and praxis, attention and calculation, recall and orientation, and the differences were statistically significant (P < 0.05) except for recall score. The results also showed the change of tumor markers were not obvious, but anxious and depressed emotions were improved. More importantly, no subjects developed with obvious adverse reactions during the study. Conclusion: The finding indicated that QXFPJYF treated digestive tract CRCI with great efficacy and safety, which improved cognitive function from several fields. Nevertheless, the current study was limited by sample and medical ethics, and which was a self-control trial, some limitations needed to be acknowledged, further high-quality research is required to explore and verify it.