The E-4B is designed to survive an EMP with systems intact and has state-of-the-art direct fire countermeasures. Although many older aircraft have been upgraded with glass cockpits, the E-4B still uses traditional analog flight instruments, as they are less susceptible to damage from an EMP blast.

The E-4B is capable of operating with a crew up to 112 people including flight and mission personnel, the largest crew of any aircraft in US Air Force history. With in-flight aerial refueling it is capable of remaining airborne for a considerable period, limited only by consumption of the engines' lubricants. In a test flight for endurance, the aircraft remained airborne and fully operational for 35.4 hours, however it was designed to remain airborne for a full week in the event of an emergency. It takes two fully loaded KC-135 tankers to fully refuel an E-4B. The E-4B has three operational decks: upper, middle, and lower.