Probiotics are most frequently derived from the natural microbiota of healthy animals. These bacteria and their metabolic products are viewed as nutritional tools for promoting animal health and productivity, disease prevention and therapy, and food safety in an era defined by increasingly widespread antimicrobial resistance in bacterial pathogens. In contemporary livestock production, antimicrobial usage is indispensable for animal welfare, and employed to enhance growth and feed efficiency. Given the importance of antimicrobials in both human and veterinary medicine, their effective replacement with direct-fed microbials or probiotics could help reduce antimicrobial use, perhaps restoring or extending the usefulness of these precious drugs against serious infections. Thus, probiotic research in livestock is rapidly evolving, aspiring to produce local and systemic health benefits on par with antimicrobials. Although many studies have clearly demonstrated the potential of probiotics to positively affect animal health and inhibit pathogens, experimental evidence suggests that probiotics’ successes are modest, conditional, strain-dependent, and transient. Here, we explore current understanding, trends, and emerging applications of probiotic research and usage in major livestock species, and highlight successes in animal health and performance.