Since the introduction of antibiotics into clinical practices in the 1940s, antibiotics have become an integral part of animal production to meet the increasing human demand for animal-derived foods. As a result, industrial-scale animal production has emerged as a hotspot for the evolution and dissemination of antibiotic resistance genes (ARGs), thereby potentially contributing to a looming public health crisis. The knowledge of ARGs in livestock systems has been greatly expanded with the recent development of rapid molecular tools. However, comprehensive reviews on ARGs in the animal industry and possible mitigation solutions are still lacking from a One Health perspective. Here we provide this review focusing on human health risks associated with the antimicrobial (antibiotic and metal) usages, ARGs in livestock animals and aquaculture systems in a One Health perspective to untangle the complexities of ARGs across animals, environments and humans. Specifically, this review covers (1) antimicrobials usages in the animal industry, (2) ARGs in animals affected by selective agents, (3) animal-to-human direct/indirect ARG transmission pathways, and (4) mitigation approaches. We highlighted the burden of using antimicrobials in animals for public and environmental health, and also the urgent needs for mitigating the spread of antibiotic resistance from the livestock and aquaculture industries.