Purpose <p>Risk factors for cancer-related cognitive impairment (CRCI) are diverse; neuroimaging instruments are recommended to complement subjective and objective cognitive assessments. This study aimed to evaluate the feasibility of a multidomain assessment protocol for CRCI in gastrointestinal cancer survivors.</p> Methods <p>Twenty-four patients with gastrointestinal cancer were scheduled for chemotherapy, and 24 healthy controls were recruited. The Functional Assessment of Cancer Therapy-cognitive function (FACT-Cog) was used to assess subjective cognitive functions. Objective cognitive function was assessed using the trail making test, auditory verbal learning test (AVLT), and verbal fluency test. Cerebral hemodynamic changes in the prefrontal cortex were measured using portable functional near-infrared spectroscopy (P-NIRS). Assessments were conducted at baseline and 6-month follow-up.</p> Results <p>Thirty-eight participants were included in the analysis. There was a statistically significant difference in AVLT-delayed recall (<i>p</i> = 0.002) in the chemotherapy group compared with the healthy control group, but no significant difference in either group for other cognitive assessments. The chemotherapy group exhibited reduced activity in the left frontal pole at 6&#xa0;months post-treatment compared to baseline (<i>p</i> = 0.018).</p> Conclusions <p>Gastrointestinal cancer survivors who receive chemotherapy may exhibit poorer delayed recall of memory functions than healthy individuals. Monitoring prefrontal cortical hemodynamics using P-NIRS during cognitive tasks is feasible for clinical application and understanding CRCI symptoms.</p> Implications for Cancer Survivors <p>These multidomain assessments are translatable to clinical practice and useful for other cancers. Additionally, the P-NIRS assessments may offer a deeper understanding on the impact of depressive symptoms and declining motivation on the cognitive function of cancer survivors.</p>