Acute myocardial infarction (AMI) is a severe disease caused by the persistent coronary artery obstruction, posing a great threat to people's health. In recent years, Toll-like receptor 4 (TLR4), an important pattern recognition receptor, has been widely studied and found to play a crucial role in AMI. This review introduces the recent progress of TLR4 in regulating the progression and prognosis of AMI, and summarizes recent TLR4-targeted therapies using clinical drugs, TLR4 inhibitors, mesenchymal stem cells, and natural bioactive molecules, providing valuable insights for addressing myocardial damage caused by AMI and improving prognosis.