Despite Cnidaria (sea anemones, corals, jellyfish, and hydroids) being the oldest venomous animal lineage, structure–function relationships, phyletic distributions, and the molecular evolutionary regimes of toxins encoded by these intriguing animals are poorly understood. Hence, we have comprehensively elucidated the phylogenetic and molecular evolutionary histories of pharmacologically characterized cnidarian toxin families, including peptide neurotoxins (voltage-gated Na+ and K+ channel-targeting toxins: NaTxs and KTxs, respectively) and pore-forming toxins (actinoporins, aerolysin-related toxins, and jellyfish toxins). We show that despite long evolutionary histories, most cnidarian toxins remain conserved under the strong influence of negative selection—a finding that is in striking contrast to the rapid evolution of toxin families in evolutionarily younger lineages, such as cone snails and advanced snakes. We also demonstrate the common evolutionary origin of type III KTxs and NaTxs in sea anemones. We show that type III KTxs have evolved from NaTxs under the regime of positive selection, and likely represent a unique evolutionary innovation of the Actinioidea lineage. We report a correlation between the accumulation of episodically adaptive sites and the emergence of novel pharmacological activities in this rapidly evolving neurotoxic clade. We also identified a few functionally important sites in other classes of neurotoxins and pore-forming toxins that experienced episodic adaptation. These findings suggest that sites that are relieved of purifying selection pressures and those responsible for toxicity constitute the evolutionary hotspots in cnidarian toxins, as long as mutations do not result in the complete loss of toxicity. Such sites may also promote changes in toxin selectivity and expand the range of molecular targets. Our findings provide fascinating insights into the evolution of venom in Cnidaria: 1) The common origin of sodium channel toxins and a subtype of potassium channel toxins in sea anemones; 2) identification of strong evolutionary constraints on most cnidarian toxin types, especially PFTs; and 3) insights into the functional diversification of various toxin types. These results emphasize the importance of understanding the molecular evolution, diversification, and phylogenetic histories of venom components, particularly in the ancient venomous lineages.