Virological research has traditionally focused on individual viruses or viral families. Advances in DNA synthesis now allow large-scale construction of individual gene products, enabling systematic exploration of the virome. Here, we developed a barcoded library of ~12,000 viral open reading frames (vORFs) from 513 viral species, which we leveraged to agnostically identify regulators of cellular proliferation and the innate and adaptive immune responses. Using this platform, we identified hundreds of viral regulators of cellular proliferation, class I MHC antigen presentation, and interferon signaling. Integrating results across these screens revealed unique phenotypic profiles and functional vORF modules, allowing the in-depth characterization of two previously uncharacterized viral proteins, MC162R and YLDV 151R, which impair class I MHC antigen presentation and IFN signaling, respectively. Together, the viral ORFeome provides a scalable framework for dissecting viral protein function across the breadth of the virome.