The community began in 1899 when two men, J.L. Avant and E.E. Blake, decided to locate a town in the Washita River Valley.
Because of governmental stipulations that an Indian could sell no more than one half of a 160-acre (0.6 km2) allotment, the men made plans to purchase 320 acres (1.3 km2) from four different Indians - Hays, Shoe-Boy, Nowahy, and Night Killer - and paid them each $2,000 for 80 acres (320,000 m2) to begin the small settlement of Washita Junction.
Congressional approval for the sale was granted in 1902 and Washita Junction quickly developed. The first businesses were the townsite office, a newspaper called the Custer County Chronicle, and the First National Bank Building. When a post office was started, the postal department would not accept the name of Washita Junction, so the town was named after the late Judge Clinton Irwin. The Frisco Railroad later turned the town into an important shipping center for the area.
Clinton also benefited from the presence of U.S. Highway 66, fostering the locally famous Pop Hicks Restaurant, which opened in 1936. The longest running restaurant on Route 66 burned down in 1999. Like most other cities and towns on Route 66, Clinton was also the home of many other tourist businesses including several restaurants, cafes, motels and gasoline service stations. Today, cross-country generally passes Clinton to the south on Interstate 40, but Clinton remains a popular tourist stop as one of the largest cities in Western Oklahoma between Oklahoma City and Amarillo, Texas. Much of the old U.S. 66 route that passed through the city is now designated as an I-40 business loop.
In 1942, the federal government built a naval airfield at nearby Burns Flat and named it Naval Air Station Clinton. During the World War II period, the population of Clinton grew to nearly 7,000 residents. In 1949, NAS Clinton was deactivated and the airfield was deeded to the City of Clinton, specifying that the land could be recaptured in case of national emergencies. Later, the government leased the site back and used it as Clinton-Sherman Air Force Base a bomber base supporting 4123rd Strategic Wing, then the 70th Bombardment Wing, Heavy of the Strategic Air Command (SAC), operating B-52 Stratofortress and KC-135 Stratotanker aircraft. Purchasing more land, the site soon expanded to more than 3,500 acres (14 km2), where both the U.S. Air Force and the U.S. Navy utilized the airfield for both operational and training purposes. When military operations were de-emphasized, the Clinton-Sherman base was designated for closure in 1969. The entire complex was deeded to the City of Clinton in 1971 and three years later became the Clinton-Sherman Industrial Airpark.
Clinton was the one time home of the National Highway 66 Association which operated for almost thirty years beginning after World War II. Though the association was disbanded in the 1980s, it instilled in Clinton an adhering interest in the Mother Road and the town became home to the first state sponsored Route 66 Museum in the nation.