Tumor progression locus 2 (TPL2) is a serine/threonine kinase that belongs to the mitogen-activated protein 3 kinase (MAP3K) family, and it plays an important role in pathogen infection. The trimer complex of TPL2, p105, and ABIN2 is essential for maintenance of TPL2 steady-state levels and host cell response to pathogens. Foot-and-mouth disease virus (FMDV) is a positive-strand RNA virus of the family Picornaviridae that encodes proteins capable of antagonizing host immune responses to achieve infection. The VP1 protein of FMDV is a multifunctional protein that can bind host cells and induce an immune response as well as cell apoptosis. However, the role and mechanisms of TPL2 in FMDV infection remain unknown. Here, we determined that FMDV infection could inhibit TPL2, p105, and ABIN2 at the transcription and protein levels, while VP1 could only inhibit TPL2, p105 and ABIN2 at protein level. TPL2 inhibited the replication of FMDV in vivo and in vitro, the 268 to 283 amino-acid region in the TPL2 kinase domain was essential for interaction with VP1. Moreover, VP1 promoted K48-linked polyubiquitination of TPL2 and degraded TPL2 by the proteasome pathway. However, VP1-induced degradation of p105 and ABIN2 was independent of proteasome, autophagy, lysosome, and caspase-dependent pathways. Further studies showed that VP1 destroyed the stability of the TPL2-p105-ABIN2 complex. Taken together, these results revealed that VP1 antagonized TPL2-meditated antivirus activity by degrading TPL2 and destroying its complex. These findings may contribute to understand FMDV-host interactions and improve development of a novel vaccine to prevent FMDV infection.Importance Virus-host interactions are critical for virus infection. This study was the first to demonstrate the antiviral effect of host TPL2 during FMDV replication by increasing production of interferons and antiviral cytokines. Both FMDV and VP1 protein can reduce host TPL2, ABIN2 and p105 to destroy TPL2-p105-ABIN2 trimer complex. VP1 interacted with TPL2 and degrade TPL2 via proteasome pathway to repress TPL2-mediated antivirus activity. This study provided new insights into FMDV immune evasion mechanisms, elucidating new informations regarding FMDV counteraction of host antivirus activity.