Purpose The Sentinel Cerebral Protection System (Sentinel‐CPS) is increasingly used in transcatheter aortic valve replacement (TAVR). However, the impact of inserting the Sentinel‐CPS inside the brain‐supplying arteries on cerebral perfusion and oxygenation is unknown. Methods Twenty patients undergoing transfemoral TAVR with (n = 10) and without (n = 10) cerebral embolic protection using the Sentinel‐CPS were prospectively observed. All patients received conscious sedation and cerebral oxygen saturation (rSO2) was continuously measured with near‐infrared spectroscopy (NIRS). The cumulative perioperative cerebral desaturation was calculated for each patient by multiplying rSO2 below an individualized desaturation threshold by time. In addition, rSO2 values at the time of Sentinel‐CPS insertion, filter positioning, and device retraction were analyzed. Results There was no significant difference in cumulative cerebral desaturation in patients with Sentinel‐CPS (median [IQR]) (0 [0/81] s%) and without (median [IQR]) (0 [0/23] s%), p = .762. A total of 6 patients (33.3%) experienced a perioperative decrease in rSO2 below the individualized desaturation threshold (n = 3 with Sentinel‐CPS, n = 3 without Sentinel‐CPS; p = 1.000). Cerebral desaturation was detected during valve deployment (n = 5) and after postdilatation (n = 1). No desaturation events occurred during Sentinel‐CPS insertion, filter positioning, or retraction. Conclusion Our pilot study revealed no difference in cumulative perioperative cerebral desaturation between TAVR with and without Sentinel‐CPS. Catheter‐ and filter‐based manipulations in the brain‐supplying arteries for Sentinel‐CPS application were not associated with a decrease of cerebral perfusion and oxygenation.