To date, the clinical use of functional near-infrared spectroscopy (NIRS) to detect cerebral ischemia has been largely limited to surgical settings, where motion artifacts are minimal. In this study, we present novel techniques to address the challenges of using NIRS to monitor ambulatory patients with kidney disease during approximately eight hours of hemodialysis (HD) treatment. People with end-stage kidney disease who require HD are at higher risk for cognitive impairment and dementia than age-matched controls. Recent studies have suggested that HD-related declines in cerebral blood flow might explain some of the adverse outcomes of HD treatment. However, there are currently no established paradigms for monitoring cerebral perfusion in real-time during HD treatment. In this study, we used NIRS to assess cerebral hemodynamic responses among 95 prevalent HD patients during two consecutive HD treatments. We observed substantial signal attenuation in our predominantly Black patient cohort that required probe modifications. We also observed consistent motion artifacts that we addressed by developing a novel NIRS methodology, called the HD cerebral oxygen demand algorithm (HD-CODA), to identify episodes when cerebral oxygen demand might be outpacing supply during HD treatment. We then examined the association between a summary measure of time spent in cerebral deoxygenation, derived using the HD-CODA, and hemodynamic and treatment-related variables. We found that this summary measure was associated with intradialytic mean arterial pressure, heart rate, and volume removal. Future studies should use the HD-CODA to implement studies of real-time NIRS monitoring for incident dialysis patients, over longer time frames, and in other dialysis modalities.