Cocaine is a common abused drug that can induce abnormal synaptic and immune responses in the central nervous system (CNS). High mobility group box 1 (HMGB1) is one kind of inflammatory molecules that is expressed both on neurons and immune cells. Previous studies of HMGB1 in the CNS have largely focused on immune function, and the role of HMGB1 in neurons and cocaine addiction remains unknown. Here, we show that cocaine exposure induced the translocation and release of HMGB1 in the nucleus accumbens (NAc) neurons. Gain and loss of HMGB1 in the NAc bidirectionally regulate cocaine‐induced conditioned place preference. From the nucleus to the cytosol, HMGB1 binds to glutamate receptor subunits (GluA2/GluN2B) on the membrane, which regulates cocaine‐induced synaptic adaptation and the formation of cocaine‐related memory. These data unveil the role of HMGB1 in neurons and provide the evidence for the HMGB1 involvement in drug addiction. During basal synaptic transmission, NSF/AP2 maintains synaptic strength by promoting AMPARs to the postsynaptic membrane. After repeated cocaine exposure, HMGB1 translocates to neuronal synaptic sites by competitively combining to GluA2, which impairs the trafficking of AMPARs and sets drug‐induced synaptic encoding.