Located in Building 30 at the Johnson Space Center (known as the Manned Spacecraft Center until 1973), the Houston MCC was first used in June 1965 for Gemini 4. It housed two primary rooms known as Mission Operation Control Rooms.

These two rooms controlled all Gemini, Apollo, Skylab, and Space Shuttle flights up to 1998. Each consisted of a four-tier auditorium, dominated by a large map screen, which, with the exception of Apollo lunar flights, had a Mercator projection of the Earth, with locations of tracking stations, and a three-orbit "sine wave" track of the spacecraft in flight. Each MOCR tier was specialized, staffed by various controllers responsible for a specific spacecraft system.

MOCR 1, housed on the second floor of Building 30, was used for Apollo 7, the Skylab and the Apollo-Soyuz Test Project missions. MOCR 2 was used for all other Gemini and Apollo flights (except Gemini 3) and was located on the third floor. As the flight control room for Apollo 11, the first manned moon landing, MOCR 2 was designated a National Historic Landmark in 1985. It was last used in 1992 as the flight control room for STS-53 and was subsequently converted back almost entirely to its Apollo-era configuration and preserved for historical purposes. Together with several support wings, it is now listed in the National Register of Historic Places as the "Apollo Mission Control Center".

When the Space Shuttle program began, the MOCRs were re-designated flight control rooms (FCR) and FCR 1 (formerly MOCR 1) became the first shuttle control room. FCR 2 was used mostly for classified Department of Defense shuttle flights, and then was remodeled to its Apollo-era configuration. From the moment a space shuttle cleared its launch tower in Florida until it landed on Earth, it was in the hands of Mission Control. When a shuttle mission was underway, its control room was staffed around the clock, usually in three shifts.

In 1992, JSC began building an extension to Building 30. The new five-story section (30 South) went operational in 1998 and houses three flight control rooms, designated Red, White, and Blue. The White FCR was used in tandem with FCR 2 for seven shuttle missions, STS-70 through STS-76, and handled all following shuttle flights through the end of the program. When not in use for the shuttle program, the White FCR was reconfigured as a backup for the ISS FCR from time to time as needed (such as during periods of construction or upgrades in the ISS FCR).

The newer section of Building 30 also houses the International Space Station Flight Control Room. The first ISS control room, originally named the Special Vehicles Operations Room (SVO), then the Blue FCR, was operational around the clock to support the ISS until the fall of 2006.

FCR 1, meanwhile, had its original consoles and tiered decking removed after STS-71, and was first converted to a "Life Sciences Center" for ISS payload control operations. After substantial remodeling, mainly with new technologies not available in 1998, ISS flight control moved into the totally-revamped FCR 1 in October 2006, due to the growth of the ISS and the international cooperation required among national control centers around the world.