The use of veterinary drugs in food‐producing animals may result in the presence of low levels of drug residues in these edible, animal‐derived foods, with potential dietary exposure to humans. Since therapeutic doses of antibiotics have been shown to affect bacterial populations in the gastrointestinal tract microbiome and can also promote the emergence of antibiotic‐resistant bacteria, there is concern that animal drugs at residue level concentrations could also perturb the intestinal microbiome composition and modify the antimicrobial resistance profile of the human intestinal microbiota. This review provides updated information on the VICH GL#36(R2), on evaluating the safety of veterinary drug residues in animal‐derived foods and their effects on the human intestinal microbiome; discusses critical research knowledge gaps and challenges in evaluating the impact of drug residues in animal‐derived foods on the human intestinal microbiome; and analyzes integrated basic and applied research approaches, currently being conducted at FDA, on studies that specifically address key regulatory science questions. Moreover, this review aims to emphasize future research needs on scientific methodology and provides general recommendations on drug inactivation, bioavailability, and antimicrobial resistance, to improve the safety evaluation and risk assessment of antimicrobial residues and their impact on the gastrointestinal microbiota, with the goal of ensuring food safety.