Objective To systematically map and compare regulatory requirements and compliance considerations for the use of human milk oligosaccharides (HMOs) in foods for special medical purposes for infants (FSMPs) across major jurisdictions, and to appraise mechanistic and clinical evidence regarding their application in hydrolyzed protein formulas, with particular attention to safety and key risk-assessment considerations.Methods Official regulations/standards and accompanying documents issued by the Codex Alimentarius Commission (CAC), the U.S. Food and Drug Administration (FDA), the European Food Safety Authority (EFSA), Food Standards Australia New Zealand (FSANZ), and Chinese regulatory authorities were systematically extracted and analyzed within a structured comparative framework. In parallel, relevant literature was retrieved from Web of Science (WoS), PubMed, and CNKI, focusing on evidence for HMO functions and on clinical use, safety, and tolerability of HMOs in hydrolyzed protein–based formulas.Results Notable cross-jurisdictional differences were identified in permitted HMO species and combinations, maximum use levels and calculation bases, scope of use and approval pathways, as well as labeling and claim boundaries. Clinically, existing studies have largely concentrated on the effects of HMO supplementation in hydrolyzed formulas on gut microbiome–related outcomes and generally indicate good tolerability; however, evidence for hard clinical endpoints such as infections and allergic outcomes remains limited, and long-term follow-up data are insufficient.Conclusion HMOs represent a feasible strategy for optimizing hydrolyzed protein–based FSMPs. Nevertheless, within applicable regulatory frameworks, further work is required to refine dose–population matching, strengthen long-term safety surveillance, and generate higher-quality clinical evidence to support precision-nutrition applications and evidence-based regulatory evaluation for infants with special medical needs.