Cold seeps host diverse microbes and viruses with numerous unexplored defense and anti-defense systems. Analysis of 3813 microbial and 13,336 viral genomes from 191 metagenomes across 17 cold seep sites reveals extensive microbial defense repertoires, with over 60% representing candidate systems. Experimental validation confirms that several candidates protect against viral infection. These defense systems frequently co-occur, suggesting potential synergistic interactions, and are broadly distributed across sediments. In response, viruses have evolved diverse anti-defense genes, and the concurrent presence of multiple viral and microbial systems highlights intricate coevolution. Functionally critical lineages, such as anaerobic methanotrophic archaea, sulfate-reducing bacteria, and diazotrophs, appear to modify their defensive strategies under ecological and environmental pressures; for example, sulfate-reducing bacteria harbor multiple Gabija systems while corresponding viruses carry anti-Gabija genes, illustrating specific coevolutionary adaptations. Overall, these findings underscore the critical role of virus-microbe interactions in shaping microbial metabolic functions and environmental adaptation in deep-sea ecosystems.