Classical swine fever virus (CSFV) infection results in highly significant economic losses. Previous studies have suggested that CSFV can be recognized by RIG-I-like receptors (RLRs) to trigger innate defenses. However, the role of mitochondrial antiviral signaling protein (MAVS), the adaptor of RLRs, is still unknown during CSFV infection. Here, we showed that CSFV infection increased MAVS expression in porcine alveolar macrophages (PAMs). Additionally, intracellular reactive oxygen species (ROS) were involved in MAVS expression in CSFV-infected PAMs. Moreover, MAVS enhanced the induction of antiviral and pro-inflammatory cytokines and apoptosis, and inhibited CSFV replication. However, CSFV still establishes a persistent infection in the host. Thus, how CSFV antagonises MAVS-mediated host cell defense was investigated. Importantly, CSFV Npro inhibited MAVS-induced interferons and pro-inflammatory cytokines and apoptosis. Furthermore, IRF3-knockdown also suppressed MAVS-induced host cell defense. Taken together, these results demonstrate that intracellular ROS is involved in CSFV-induced MAVS expression and MAVS induces antiviral cytokines and apoptosis to inhibit CSFV replication while CSFV Npro inhibits MAVS-mediated host cell defenses possibly through degradation of IRF3. These data offer novel insights into the immunomodulatory effects of CSFV infection on the host innate response.