In this study, hot water extract from sea buckthorn (Hippophae rhamnoides L.) leaves fermented with Hericium erinaceum mycelium (SBT-HE) was assessed for protection against oxidative modification of biological macromolecules and cell death. Antioxidant activity of SBT-HE was evaluated based on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical, and peroxyl radical scavenging assays. SBT-HE showed 65.06% DPPH radical scavenging activity at 500 μg/mL, 98.83% ABTS radical scavenging activity at 50 μg/mL, and 44.03% peroxyl radical scavenging activity at 100 μg/mL. SBT-HE significantly inhibited DNA strand breakage induced by peroxyl radical. SBT-HE also prevented peroxyl radical-mediated human serum albumin modification. SBT-HE effectively inhibited H2O2-induced cell death and significantly increased cell survival by 21.59% at 100 μg/mL. SBT-HE also reduced intracellular reactive oxygen species levels in H₂O₂-treated cells. The results suggest that SBT-HE can contribute to antioxidant activity and protect cells from oxidative stress-induced cell injury.