Wound healing is a complex and dynamic process supported by several cellular events. Around 13 million individuals globally suffer from chronic wounds yearly, for which dressings with excellent antimicrobial activity and cell viability (>70%, as per ISO 10993) are needed. Excessive use of silver can cause cytotoxicity and has been linked to increasing antimicrobial resistance. In this study, HDI Ag foam was synthesized using a safer hexamethylene diisocyanate-based prepolymer (HDI prepolymer) instead of commonly used diisocyanates like TDI and MDI and substantially lower Ag content than that incorporated in other Ag foams. In vitro characteristics of the HDI Ag foam were evaluated in comparison with leading clinically-used foam-based dressings. All dressings underwent a detailed characterization in accordance with industrially accepted BS EN 13726 standards. The HDI Ag foam exhibited highest antimicrobial efficiency against Staphylococcus aureus and Pseudomonas aeruginosa (static condition), with the lowest amount of Ag (0.2 wt%) on the wound contact surface. The extracts from HDI Ag foam showed superior cell viability (>70%), when tested on the L929 mouse fibroblast cell line. Measurements of moisture vapour transmission, fluid handling, physico-chemical and mechanical properties ensured that the HDI foam was clinically acceptable for chronic wound patients.