Fuel cell electric vehicles offer an attractive option for decarbonizing long-haul on-road transport. However, there are still several barriers to widespread adoption of hydrogen-fueled fuel cells for this application. A primary contributor to fuel cell system costs and maintenance requirements is the air management components. This study focuses on the development of a durable and efficient air management system for heavy duty vehicle applications as part of a cooperative research project funded by the Department of Energy’s Hydrogen and Fuel Cell Technologies Office. The designed air management system incorporates a novel two stage filtration system for ultra-purified air entering the fuel cell stack, an innovative water-lubricated bearing and electrically-assisted variable turbine geometry turbocharger, charge air cooler, and humidifier. To achieve the ambitious Department of Energy project goals for efficiency and durability, a system-level optimization approach has been employed. 1D simulations of the optimized system compared to a baseline e-compressor showed a >40% reduction in e-motor power at steady-state conditions and a >30% reduction in e-motor energy consumption in a transient cycle, as well as enhanced durability vs. state-of-the-art solutions. This innovative air management system approach, by increasing efficiency and promoting durability of both balance of plant components and the stack itself, can help significantly reduce total cost of ownership for HD fuel cell vehicles.