Background: Highly Pathogenic Avian Influenza A (subtype H5N1) poses a threat to human health, and its pandemic potential emphasizes the need to better understand detailed reported transmission pathways to humans. Existing literature is outdated or lacks detailed, comprehensive analysis of the range of transmission routes and how the virus may enter the human body.

Objective: To comprehensively map all reported H5N1 transmission pathways to humans, as well as viral entry routes.

Methods: CINAHL, Embase, MEDLINE, Scopus, PubMed, grey literature, and reference lists (of included studies) were searched up to October 29th, 2025, with no language restrictions. Observational studies and grey literature reporting H5N1 transmission evidence to humans were included. Two reviewers conducted duplicate screening independently (two of three reviewers per record). One reviewer completed data extraction, which was cross-verified for accuracy by a second. Findings were summarized narratively.

Results: 120 sources met inclusion criteria (70 studies, 50 grey literature). Reported H5N1 transmission pathways were classified into animal-to-human (109 of 120 sources, 90.8%; including poultry-to-human in 100 sources [83.3%] and cattle-to-human in nine sources [7.5%]), environment-to-human (32 of 120 sources, 26.7%), and human-to-human (14 of 120 sources, 11.7%). Reported transmission pathways were further classified as direct or indirect contact, synthesized, and linked to suspected routes of human entry, including mucosal entry (eyes, nose, mouth), inhalation of aerosols or droplets, ingestion, and percutaneous exposure. Entry routes are biologically plausible and do not imply relative likelihood or causal attribution.

Conclusions: There are multiple reported pathways of H5N1 exposure, and a single pathway may involve multiple ways to infect humans. Further research is needed to determine causal mechanisms, identify specific risk factors and measures of association, and strengthen evidence-based prevention strategies.