Background: Hemodialysis (HD) patients frequently suffer from severe anemia caused by various hemorrhagic disorders in addition to renal anemia. Intradialytic blood transfusion is sometimes performed; however, the cerebral oxygenation changes associated with this procedure remain unclear. Methods: Sixteen HD patients with severe anemia who required intradialytic blood transfusion were included (12 men and 4 women; mean age, 64.8 ± 9.8 years). Cerebral regional oxygen saturation (rSO2) was monitored using near-infrared spectroscopy, and cerebral fractional oxygen extraction (FOE) was calculated before and after HD. Twenty-five HD patients with well-maintained hemoglobin (Hb) levels were included as a control group. Results: Cerebral rSO2 values were significantly lower in HD patients with severe anemia than in the control group (42.4 ± 9.9 vs. 52.5 ± 8.5%, p = 0.001). Following intradialytic blood transfusion (385 ± 140 mL of concentrated red blood cells), Hb levels significantly increased (from 7.2 ± 0.9 to 9.1 ± 1.1 g/dL, p < 0.001), and cerebral rSO2 values significantly improved after HD (from 42.4 ± 9.9 to 46.3 ± 9.0%, p < 0.001). Cerebral FOE values before HD in patients with severe anemia were significantly higher than those in the control group (severe anemia, 0.56 ± 0.10; controls, 0.45 ± 0.08; p < 0.001). After HD with intradialytic blood transfusion, these values significantly decreased (0.52 ± 0.09 after HD versus 0.56 ± 0.10 before HD, p = 0.002). Conclusion: HD patients with severe anemia represented cerebral oxygen metabolism deterioration, which could be significantly improved by intradialytic blood transfusion.