The Ford F-350 Super Duty 4WD was first introduced in the F-Series line of pickups in 1948. However, the F-350 badge did not appear until the third generation of the line in 1957. The F-350 quickly became a bestseller for drivers that needed a truck that could handle almost any load. With impressive towing and hauling capabilities, the Ford F-350 was commonly used as a work truck in the construction industry and as part of farm fleets. Though Ford introduced a Super Duty truck in 1987, the F-350 pickup did not acquire the Super Duty 4WD trim until 1999.

The tenth generation of the F-Series got started with the F-350 Super Duty 4WD. This model was equipped to handle the most demanding towing and hauling, but featured 4WD for those that did not use the pickup in rough terrain. The Super Duty was manufactured at the Blue Diamond Truck Company in Escobedo, Mexico. Buyers could choose from a regular cab or super cab, and also had the option of Styleside or Flareside beds. The distinction between Styleside and Flareside meant either protruding wheel wells and more bed space or a sleek design with wheel wells inside the truck bed. The F-350 Super Duty was available with a wide variety of engine models ranging from a 6.8L Triton V10 to 6.0L Power Stroke turbo-diesel V8.

In 2007, the Ford F-350 Super Duty was ranked Fleet Truck of the Year in its category because of its superior handling and capabilities. Many buyers were also impressed with the truck's sleek, understated exterior. The 2009 model year is bringing about big changes for the F-350. The exterior is getting a more chiseled and contemporary style, while the front end appears more aggressive and commanding. Though several of the F-Series models are available as electric hybrid editions, the driving demands of the F-350 do not make it an appropriate model to utilize the current hybrid technology. Ford claims that as hybrid technology advances, the F-350 might eventually be available as a hybrid.

While the Ford F-350 Super Duty 4WD has been primarily used as a commercial model, many films and television shows have given it a prominent role. Movies like 21 Grams, High Crimes, Return to Sender, and Live Free or Die Hard starring Bruce Willis have utilized the pickup. Television programs that featured the model include Desperate Housewives, Reno 911!, Law & Order: Criminal Intent, and the Disney Channel's Even Stevens.