Neuropathic pain (NP) is an intolerable pain syndrome that arises from continuous inflammation and excitability after nerve injury. Only a few NP therapeutics are currently available, and all of them do not provide adequate pain relief. Herein, we report the discovery of a selective and potent inhibitor of the bromodomain and extra-terminal (BET) proteins for reducing neuroinflammation and excitability to treat NP. Starting with the screening hit from an in-house compound library, iterative optimization resulted in the potent BET inhibitor with a unique binding mode and a novel chemical structure. exhibits excellent BET selectivity and favorable drug-like properties. In mice with spared nerve injury, significantly alleviated mechanical hypersensitivity by inhibiting pro-inflammatory cytokine expression and reducing excitability. Collectively, these results implicate that is a promising agent for the treatment of NP.