The first C-5A Galaxy (#66-8303) was "rolled out" on 2 March 1968. On June 30th 1968 Lockheed-Georgia Co. began flight testing its new Galaxy C-5A heavy transport with the aircrafts first flight taking to the air under the call-sign "Allen-zero-three-heavy", upon completion of testing the first C-5A was transferred to the Transitional Training Unit at Altus Air Force Base, OK, in December 1969. Lockheed then delivered the first operational Galaxy to the 437th Airlift Wing, Charleston Air Force Base, SC, in June 1970. C-5s are stationed at Altus AFB, OK; Dover AFB, DE; and Travis AFB, CA. AMC transferred some C-5s to the Air Reserve components starting with Kelly AFB, Texas, in 1985; followed by Stewart Air National Guard Base, NY; and Westover Air Reserve Base, MA.

In the mid-1970s, wing cracks were found throughout the fleet. Consequently, all C-5A aircraft were restricted to a maximum of 50,000 pounds (22,680kg) of cargo each. To increase their lifting capability and service life, 77 C-5As underwent a re-winging program from 1981 to 1987. (In the redesigned wing, a new aluminum alloy was used that didn't exist ten years prior.) The final re-winged C-5A was delivered in July 1986.

The first C-5B incorporating significant improvements such as strengthened wings and updated avionics was delivered to Altus Air Force Base in January 1986. C-5 production concluded with delivery of the last "B" model aircraft in April 1989.

In March 1989, the last of 50 C-5B aircraft was added to the 76 C-5As in the Air Force's airlift force structure. The C-5B includes all C-5A improvements as well as more than 100 additional system modifications to improve reliability and maintainability. All 50 C-5Bs are scheduled to remain in the active-duty force, shared by comparably sized and collocated Air Force Reserve Associate units.

Based on a recent study showing 80 percent of the C-5 airframe service life remaining, AMC began an aggressive program to modernize the C-5. The C-5 Avionics Modernization Program began in 1998 and includes upgrading avionics to Global Air Traffic Management compliance, improving navigation and safety equipment, and installing a new autopilot system. Another part of the plan is a comprehensive re-engining and reliability improvement program, which includes new General Electric CF6-50 engines, pylons and auxiliary power units, with upgrades to aircraft skin and frame, landing gear and the pressurization system. This C-5M modernization program will restore aircraft reliability and maintainability, maintain structural and system integrity, reduce cost of ownership and increase operational capability well into the 21st century. Unlike its Russian counterpart, the civilian- and military-operated Antonov An-124, use of the C-5 is confined entirely to the military sector.