This disclosure relates to a design and manufacturing system for protective patient footwear, as well as related methods. The system includes suitable hardware, software, and related peripherals, which function to acquire data related to the patient's particular footwear needs, such as by three-dimensional scanning. A design subsystem interfaces with the inputted data to permit the resulting design to reflect particular foot conditions in the design and subsequent manufacturing process. A manufacturing subsystem receives the resulting design and includes hardware and software to manufacture the protective patient footwear.