Mycoplasma hyopneumoniae (M. hyopneumoniae, Mhp) is an etiological agent that causes mycoplasma pneumonia of swine (MPS), this is a chronic respiratory disease present in every major swine-producing country worldwide. It is well elucidated, Mhp infections may downregulate the host immune system and enhance the infection and replication of other pathogens. However, the mechanisms of interaction between Mhp and other pathogens is still missing. Though, additional studies have reported that several cofactors such as bacteria, vaccination failure, stress or crowing and other swine viruses in combination with Mhp, lead to MPS. Aside these cofactors, the co-infection of Mhp with other viruses, such as Porcine Circovirus, Porcine Reproductive and Respiratory Syndrome Virus, Swine Influenza Virus, Pseudorabies Virus, and other bacteria, such as Pasteurella multocida, Actinobacillus pleuropneumoniae have been widely studied for many years. In this review, we summarized the co-infection of Mhp with other swine pathogens based our studies made, the co-infection with other viruses and bacteria, revealed the interaction mechanism of different pathogens with Mhp in the host