Anthropogenic effects on the environment, ecology, and biodiversity of animals are not exclusive to the Anthropocene but extend deep into antiquity. In fact, many archaeologists and historical ecologists argue that the complex interplay between humans and their environment for the past millennia have shaped the Anthropocene. Archaeologists, in particular, have long recognized humans as the ultimate niche constructors given their ability to significantly alter the environment to meet their needs, which in turn creates and influences other natural selective pressures. Such effects have been observed within early human-animal interactions and the resulting transition to animal domestication. In addition, it has been argued that these early human alterations to both our environment and animals fostered the rise in zoonotic diseases. New biomolecular tools and advances in the “-omics” coupled with the archaeological record can provide meaningful snapshots in time to address how humans have facilitated changes to domestication patterns and consequentially animal health and the spread of zoonotic diseases. As such, this dissertation research takes a theoretical, methodological, and data driven approach to address human-animal interactions and the long dynamic nature of anthropogenic disruptions. The impact of this dissertation is threefold: increasing our understanding of human-made environmental impacts, increasing the recognition of natural history collections and biorepositories as valuable resources to address historical shifts in biodiversity and ecologies due to human activity, and the incorporation of microbiome data in broadening our understanding of human-animal interactions. As a result, this dissertation research offers a transdisciplinary approach that will fill the gap in studies of past human-animal interactions.