African swine fever (ASF) causes high morbidity and mortality of both domestic pigs and wild boars and severely impacts the swine industry worldwide. ASF virus (ASFV), the etiologic agent of ASF epidemics, mainly infects myeloid cells in swine mononuclear phagocyte system (MPS), including blood-circulating monocytes, tissue-resident macrophages, and dendritic cells (DCs). Since their significant roles in bridging host innate and adaptive immunity, these cells provide ASFV with favorable targets to manipulate and block their antiviral activities, leading to immune escape and immunosuppression. To date, vaccines are still being regarded as the most promising measure to prevent and control ASF outbreaks. However, ASF vaccine development is delayed and limited by existing knowledge gaps in viral immune evasion, pathogenesis, etc. Recent studies have revealed that ASFV can employ diverse strategies to interrupt the host defense mechanisms via abundant self-encoded proteins. Thus, this review mainly focuses on the antagonisms of ASFV-encoded proteins towards IFN-I production, IFN-induced antiviral response, NLRP3 inflammasome activation, and GSDMD-mediated pyroptosis. Additionally, we also make a brief discussion concerning the potential challenges in future development of ASF vaccine.