Introduction Hemodialysis (HD) patients have significant burden of cerebral ischemic pathology noted on brain imaging. These ischemic type lesions maybe due to cerebral hypoperfusion that may be occurring during blood pressure (BP) fluctuations commonly noted during HD sessions. We evaluated changes in cerebral perfusion and measured an index of cerebral autoregulation (CA index) during HD to identify potential risk factors for intradialytic decline in cerebral perfusion and impaired cerebral autoregulation. Methods In this cross‐sectional study, we included HD patients age 50 years or older receiving conventional in‐center HD. We measured cerebral perfusion during HD, using cerebral oximetry, and calculated the correlation between cerebral perfusion and BP during HD as an index of CA. We measured the association between potential risk factors for intradialytic decline in cerebral perfusion and CA index. Findings We included 32 participants and 118 HD sessions in our analysis. The mean ± SD decline in cerebral oxygen saturation during HD was 6.5% ± 2.9% with a relative decline from baseline values of 9.2% ± 4.4%. Greater drop in systolic BP (SBP) during HD was associated with decline in cerebral oxygen saturation, p = 0.02. Impaired CA index was noted in 37.3% of HD sessions. Having diabetes and >20 mmHg drop in SBP during HD were associated with increased (worse) CA index with an increase of 0.24 95%CI [0.06, 0.41] for diabetes and increase of 0.43 95%CI [0.27, 0.56] for a >20 mmHg drop in SBP during HD. Discussion Cerebral perfusion can decline during HD and is associated with changes in systemic BP. This may be due to impaired cerebral autoregulation in HD patients. Risk factors for worse CA index include diabetes and >20 mmHg drop in SBP during HD. This study highlights the risk of intradialytic decline in cerebral perfusion and impaired cerebral autoregulation in HD patients.