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Since Darwin, many evolutionary and behavioral researchers have considered the role of phenotypic traits that favor the domestication of nonhuman animals. Among such proposed traits are a species’ social structure, level of intra- and interspecific agonistic interactions, sociosexual behaviors, parental strategies, reaction to humans, habitat preference, dietary habits, developmental trajectories, and utility to humans. However, little to no comparative phylogenetic evidence exists concerning the importance of these attributes for the domestication of animals. Moreover, rather than considering domestication as a dichotomous event (non-domesticated vs. domesticated), humans and their potential domesticates encountered numerous socioecological challenges/obstacles during the domestication process before reaching the stage of full domestication. The present study explored the influence of adult body mass, gregariousness, dietary breadth, and reaction to humans on the domestication process of ungulates. The phylogenetic comparative model revealed that capture myopathy (CM), as a proxy for reaction to humans, negatively and significantly influenced the domestication process. The present paper also explored the evolution of CM in equine species in response to the presence of large carnivoran predators during the Pleistocene. Ecologies that preserved most of the large carnivoran predators of equine species also featured more equine taxa with CM (e.g., zebras), which were thus less suitable for domestication.