Infectomics, a novel way to globally and comprehensively understand the interactions between microbial pathogens and their hosts, has significantly expanded understanding of the microbial infections. The infectomics view of viral–host interactions on the viral perspective principally focuses on gene acquisition, deletion, and point mutation, while traditional antiviral drug discovery concentrates on viral encoding proteins. Recently, high-throughput technologies, such as mass spectrometry-based proteomics, activity-based protein profiling, microarray analysis, yeast two-hybrid assay, small interfering RNA screening, and micro RNA profiling, have been gradually employed in the research of virus–host interactions. Besides, signaling pathways and cellular processes involved in viral–host interactions provide new insights of infectomics in antiviral drug discovery. In this review, we summarize related infectomics approaches in the studies of virus–host interactions, which shed light on the development of novel antiviral drug targets screening.