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Background The nucleus accumbens in the midbrain dopamine limbic system plays a key role in cocaine addiction. Toll-like receptors (TLRs) are important pattern-recognition receptors (PPRs) in the innate immune system that are also involved in drug dependence; however, the detailed mechanism is largely unknown. Methods The present study was designed to investigate the potential role of TLR3 in cocaine addiction. Cocaine-induced conditioned place preference (CPP), locomotor activity, and self-administration were used to determine the effects of TLR3 in the rewarding properties of cocaine. Lentivirus-mediated re-expression of Tlr3 (LV-TLR3) was applied to determine if restoration of TLR3 expression in the NAc is sufficient to restore the cocaine effect in TLR3−/− mice. The protein levels of phospho-NF-κB p65, IKKβ, and p-IκBα both in the cytoplasm and nucleus of cocaine-induced CPP mice were detected by Western blot. Results We showed that both TLR3 deficiency and intra-NAc injection of TLR3 inhibitors significantly attenuated cocaine-induced CPP, locomotor activity, and self-administration in mice. Importantly, the TLR3−/− mice that received intra-NAc injection of LV-TLR3 displayed significant increases in cocaine-induced CPP and locomotor activity. Finally, we found that TLR3 inhibitor reverted cocaine-induced upregulation of phospho-NF-κB p65, IKKβ, and p-IκBα. Conclusions Taken together, our results describe that TLR3 modulates cocaine-induced behaviors and provide further evidence supporting a role for central pro-inflammatory immune signaling in drug reward. We propose that TLR3 blockade could be a novel approach to treat cocaine addiction. Electronic supplementary material The online version of this article (10.1186/s12974-018-1130-8) contains supplementary material, which is available to authorized users.