During World War II, four separate government agencies controlled sea transportation. In 1949, the Military Sea Transportation Service became the single managing agency for the Department of Defense's ocean transportation needs. The command assumed responsibility for providing sealift and ocean transportation for all military services as well as for other government agencies.

Only nine months after its creation, MSTS responded to the challenge of the Korean War. On July 6, 1950, only 11 days after the initial invasion of South Korea by communist North Korean troops, MSTS transported the 24th Infantry Division and its equipment from Japan to Pusan, South Korea, for duty.

During the Vietnam War, MSTS was renamed Military Sealift Command. Between 1965 and 1969, MSC transported nearly 54 million tons of combat equipment and supplies and nearly 8 million tons of fuel to Vietnam. MSC ships also transported troops to Vietnam. The Vietnam era marked the last use of MSC troop ships. Now, U.S. troops are primarily transported to theater by air.

Through the 1970s and 1980s, MSC provided the Department of Defense with ocean transportation in support of U.S. deterrent efforts during the Cold War years.

During the first Persian Gulf War's Operations Desert Shield and Desert Storm, MSC distinguished itself as the largest source of defense transportation of any nation involved. MSC ships delivered more than 12 million tons of wheeled and tracked vehicles, helicopters, ammunition, dry cargo, fuel and other supplies and equipment during the war. At the height of the war, MSC managed more than 230 government-owned and chartered ships.

Since Sept. 11, 2001, MSC ships have played a vital and continuing role in contingency operations around the world. As of January 2013, MSC ships delivered more than 25.7 billion gallons of fuel and moved 126.2 million square feet of combat equipment and supplies to U.S. and coalition forces engaged in operations supporting Iraq and Afghanistan.

In addition, MSC, the Navy and several non-governmental organizations have treated hundreds of thousands of patients in hospital ship deployments worldwide.