Patrick AFB began in World War Two as Naval Air Station Banana River, a rapidly erected subordinate base for NAS Jacksonville. NAS Banana River's mission was primarily anti-submarine patrolling with patrol bomber seaplanes observation blimps - not as silly as it might sound; the blimps had fantastic loiter time, could hover, were quiet even with engines on and silent with engines off, difficult to spot in any kind of haze, and had low fuel demands. NAS Banana River also hosted an aviation navigation training center, air search and rescue operations, seaplane pilot training, patrol bomber bombardier training, communications research, landing gear testing, and a repair and maintenance depot. NAS Banana River continued operations for two years after the close of World War Two, and was inactivated after a wind-down period in late 1947.

The field was transferred to the US Air Force in late 1948 and named Joint Long Range Proving Ground, and has since that time, except for two years, been the home base for the 45th Space Wing and various subordinate units, under a number of different unit names and configurations.

In 1950 the Joint Long Range Proving Ground was renamed Patrick Air Force Base, after Major General Mason Patrick, US Army General, engineer, pilot, and creator of the US Army Air Corps from the prior US Army Air Service; General Patrick had supported the vision of a strong US military air arm since his days in World War One as commander of the Air Service, when he brought the service into proper military order.

Starting in the 1950s and continuing to the present, Patrick AFB has been the administrative and operations base for the Eastern Range rocket testing facilities, Cape Canaveral Air Force Station (Cape Kennedy from 1963 to 1973), the Kennedy Space Center (which are both north of the base on a separate barrier island), and several aerospace and guided missile test units. Much of the operational management of the US Space Program has been conducted with or from Patrick AFB. The Delta, Atlas, and Saturn rocket series have all been at least partially developed, and launched, under units of Patrick AFB. Patrick units have also supported the space programs of the European Space Agency.

The rocket, missile, and space program support mission called for a general expansion of base housing and other facilities, and the base underwent a series of expansions.

In the mid 1960s Patrick was the setting for the I Dream of Jeannie TV show; the exterior shots for astronaut Captain (later Major) Anthony Nelson's station were of Patrick AFB (no cast were ever on site, thought).

Patrick AFB is also home of the Air Force Technical Applications Center, which monitors global nuclear tests in support of several international nuclear test bans and to keep a watch for nuclear testing by non-signatory nations. In 1964 the AFTAC (or its predecessor) detected China's early nuclear testing; in 1968 AFTAC detected a Soviet nuclear submarine accident and sinking; in 1974 AFTAC detected India's first nuclear test; Pakistan's nuclear testing was detected by AFTAC in 1998; and more recently North Korea's nuclear tests were detected in 2006. AFTAC also sifts surveillance information for suspected but unconfirmed nuclear explosions.

1970 saw the establishment of what is today the Defense Equal Opportunity Management Institute at Patrick AFB, dedicated to fully and smoothly integrating all service personnel into military service regardless of race, sex, or religion.

The 9/11 attacks required the heavily used, four-lane Florida State Road A1A, which runs directly in front of Patrick's Air Force Technical Applications Center, be temporarily closed.

The 920th Rescue Wing was relocated to Patrick AFB in 1997, having been temporarily housed there since the destruction of Homestead AFB in 1993. The 920th has supported space program missions since the earliest days of manned space flight, as well as hurricane relief efforts, and service rescue and extraction for Navy and Army operations worldwide, from Operation Desert Shield to the modern day. The 920th's history goes back to the Cuban Missile Crisis and Berlin Crisis of the early 1960s.