α-Cyperone has anti-inflammatory activities, but its effects on spinal cord injury (SCI) remain obscure. Thus, this study attempts to investigate the effects and modulatory mechanisms of α-Cyperone on SCI.An SCI model was established in rats which were further treated with α-Cyperone. Basso-Beattie-Bresnahan (BBB) scoring was used to assess motor rehabilitation of rats modeled with SCI. The spinal cord tissues were collected, and the effect of α-Cyperone on the histopathology of rats modeled with SCI was detected by hematoxylin-eosin staining. Rat primary cortical neuron was stimulated with H2O2 and further treated with α-Cyperone and nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385. The levels of Nrf2, interleukin-6 (IL-6), nuclear factor kappa B (NF-κB), Akt, toll-like receptor 4 (TLR4), and tumor necrosis factor-alpha (TNF-α) were detected by immunofluorescence staining and western blotting.α-Cyperone elevated the BBB score and ameliorated the damage of spinal cord tissue in rats modeled with SCI. The levels of IL-6, Nrf2, NF-κB, TLR4, and TNF-α were upregulated, whereas that of Akt was downregulated in rats and cells modeled with SCI. Furthermore, α-Cyperone diminished the levels of IL-6, NF-κB, TLR4, and TNF-α, while augmenting those of Nrf2 and Akt in rats and cells modeled with SCI. ML385 inhibited the Nrf2 level that had been promoted by α-Cyperone in the nucleus and elevated the Nrf2 level that had been suppressed by α-Cyperone in the cytosol of cells modeled with SCI. ML385 increased the levels of IL-6, NF-κB, TLR4, and TNF-α that had been inhibited by α-Cyperone and decreased the Akt level that had been enhanced by α-Cyperone in cells modeled with SCI.α-Cyperone suppressed SCI-induced inflammation and spinal cord tissue damage via activating Akt/Nrf2 and suppressing NF-κB pathways.Copyright © 2022 Elsevier Inc. All rights reserved.