The human gastrointestinal tract is a habitat for diverse microbial taxa including archaea. Here, by establishing a unique in silico workflow, we resolve the identities of gut-specific archaeal proteins. We developed a strategy for protein functional annotation employing the most recent protein sequence- and structure-based approaches such as AlphaFold2, trRosetta, ProFunc and DeepFri. Where sequence-based approaches failed, our strategy led to the identification of archaeal proteins. Here, we identify a subset of archaeal gut-specific proteins involved in various defense strategies and virulence. For instance, BglII restriction endonuclease is the most commonly occurring unique protein involved in host genome defense against invading DNA. Furthermore, multiple adhesin-like proteins which likely facilitate archaeal cell adhesion to surfaces. We also resolve functions assisting degradation of toxic substances via propanediol utilization protein pduA. We identify a variety of glycosyltransferases involved in both N-linked glycosylation and O-glycosylation. In addition, we highlight several types of glycosyltransferases encoded by Methanobrevibacter smithii which may possibly be involved in the construction of O-glycosylated surfaces, beneficial for proliferation within the human intestine. Finally, we demonstrate the presence of proteins not only modulating interdomain horizontal gene transfer but also those possibly being the result of such genetic material exchange. In this context, we present evidence on horizontally transferred sporulation stage V proteins AE and AD from Clostridium species to M. smithii. In summary, our tailored in silico workflow allows the characterization of previously undescribed archaeal proteins which are specific to the gut environment and, thus, human microbiome function.