Ischemia-reperfusion injury (IRI) is an inevitable pathological process during donation after circulatory death (DCD) liver transplantation, which contributes to serious damage to the graft. Oxidative stress, inflammation and apoptosis are all fatal causes of IRI of the liver. Hypothermic oxygenated perfusion (HOPE), as an emerging dynamic preservation technology, has a more significant effect on reducing DCD liver IRI than static cold storage (CS) mainly by regulating oxidative stress and inflammation. To further enhance the effect of HOPE and reveal its underlying mechanisms, investigators have recently combined HOPE with various methods. Excessive activation of the TLR/MyD88 signaling pathway can lead to severe immune inflammatory response. TJ-M2010-5 (TJ-5), a novel thiazaol-aminoramification MyD88 inhibitor, plays an essential role in the treatment of various diseases or pathological injuries in mice, such as hepatocellular carcinoma, acute liver injury and myocardial IRI. However, little is known about the role of TJ-5 in HOPE alleviating DCD liver IRI. Herein, we sought to investigate the role of HOPE combined with TJ-5 in reducing DCD liver IRI. We found that HOPE combined with TJ-5 significantly reduced oxidative stress, lessened inflammation, and decreased apoptosis during DCD liver IRI. Furthermore, HOPE combined with TJ-5 exerted their effects by inhibiting the TLR/MyD88 signaling pathway. Overall, these results demonstrated that HOPE combined with TJ-5 has a significant effect on alleviating DCD liver IRI. Therefore, the combined application of HOPE and TJ-5 may be an available and valid treatment option for DCD liver IRI.