Simple SummaryCnidarians (such as corals, anemones, jellyfish) are ancient and successful animals. Previous studies have offered a variety of explanations for the adaptive success of certain cnidarian taxa. However, common strategies for the long-term persistence of cnidarians have not been identified. One factor that may contribute to their evolutionary success of the lineage is the nematocyst, a sting organelle able to deliver venom into prey or enemies. Using bioinformatics analyses, we aimed to quantitatively investigate the role of nematocysts in cnidarian adaptation. We identified the extensive species-specific adaptation in nematocyst proteins (NEMs) and demonstrate that both a unique evolutionary pattern of NEMs and the long evolutionary lag between nematocysts and cnidarians support their key adaptive role. Further, we find NEMs experience approximately 50% more adaptive changes on average compared to non-NEMs, and positively selected cnidarian-conserved proteins are enriched in NEMs. These results support a key role of nematocysts in successful cnidarian adaptation and provide a general quantitative framework for assessing the role of a phenotypic novelty in adaptation. Moreover, the findings will be critical for reassessing the evolutionary history of many established models, enhancing our understanding of both the mechanisms and evolutionary preference of adaptive evolution.Nematocysts are secretory organelles in cnidarians that play important roles in predation, defense, locomotion, and host invasion. However, the extent to which nematocysts contribute to adaptation and the mechanisms underlying nematocyst evolution are unclear. Here, we investigated the role of the nematocyst in cnidarian evolution based on eight nematocyst proteomes and 110 cnidarian transcriptomes/genomes. We detected extensive species-specific adaptive mutations in nematocyst proteins (NEMs) and evidence for decentralized evolution, in which most evolutionary events involved non-core NEMs, reflecting the rapid diversification of NEMs in cnidarians. Moreover, there was a 33–55 million year macroevolutionary lag between nematocyst evolution and the main phases of cnidarian diversification, suggesting that the nematocyst can act as a driving force in evolution. Quantitative analysis revealed an excess of adaptive changes in NEMs and enrichment for positively selected conserved NEMs. Together, these findings suggest that nematocysts may be key to the adaptive success of cnidarians and provide a reference for quantitative analyses of the roles of phenotypic novelties in adaptation.