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ABSTRACT African swine fever virus (ASFV) causes severe acute hemorrhagic disease with high mortality in domestic pigs but minimal or no symptoms to warthogs, for which the underlying mechanism remains elusive. ASFV encodes numerous proteins to disturb host immune responses via interacting with host proteins. In this study, we deciphered the comprehensive protein-protein interaction (PPI) network between ASFV and host immune pathways by the recombination-based library vs library high-throughput yeast two-hybrid screening. This PPI network contains both ASFV-host PPI and ASFV-ASFV PPI information, providing a comprehensive ASFV-host interactome landscape. We further explored the ASFV-host PPI difference between domestic pigs and warthogs. Moreover, the inhibitory effect of ASFV proteins in the PPI with cGAS-STING pathway on IFN-I and NF-κB promoter activity was screened to investigate the ASFV-host PPI functions. Our work will help the exploration of ASFV pathogenesis and the development of anti-ASFV vaccine and ASFV-resistant transgenic pigs.IMPORTANCEAfrican swine fever (ASF), caused by African swine fever virus (ASFV), has become a major crisis for the pork industry in recent years. The mechanism for ASFV pathology and the clinical symptoms difference of ASF between domestic pigs and reservoir hosts remain to be elucidated. We deciphered the comprehensive protein-protein interaction (PPI) network between ASFV and host immune pathways. The intensive PPI network contained both ASFV-host immune pathway PPI and ASFV-ASFV PPI information, providing a comprehensive ASFV-host interaction landscape. Furthermore, the ASFV-host PPI difference between domestic pigs and warthogs was explored, which will be instructive for exploring essential candidates involved in ASFV pathology. Moreover, we screened the inhibitory effect of ASFV proteins in the PPI with cGAS-STING pathway on IFN-I and NF-κB, further providing possible functions of ASFV-host PPI network in innate immune regulation.