The pathogenesis of Parkinson's disease (PD) is closely linked to the massive presence of Lewy vesicles and Lewy axons in the cytoplasm of neurons, mainly consisting of α-synuclein (αS). Norepinephrine (NE), whose secretion can be increased by exercise, has been demonstrated to prevent the fibrillation of αS and to break down the mature αS fibrils. In this work, we focus on the influence of protonation on the inhibitory ability of NE by using amyloid core fragment αS71-82 as a template. All-atom replica-exchange molecular dynamics simulations (accumulating to 33.6 μs) in explicit water were performed to explore the inhibitory effect of protonated and nonprotonated NE on αS oligomerization. Our results show that NE/NE+ can lead to a significant decrease in β-sheet content with increasing temperature, while isolated αS maintains relatively higher β-sheet conformations until 363 K, implying that both NE and NE+ can lower the critical temperature required for αS fibril decomposition. NE and NE+ also lead to the formation of less compact αS oligomers by preventing the backbone hydrogen bonds and the side-chain packing. The protonation would affect the binding affinity, interaction modes, and binding intensity of NE with αS. Interesting, NE and NE+ have a distinct binding free energy in the electrostatic and solvation terms, which mostly counter each other and produce a weak binding intensity with αS. Our work contributes to a better understanding of the inhibitory mechanism of NE and NE+ on αS oligomerization relevant to PD pathogenesis, which may provide clues for the design of antiamyloid medicine.