Derived from the smaller F-Series pickup trucks, the medium-duty range is currently in its eighth generation.

The medium-duty F-Series has been used for an extensive number of applications, offered as a straight (rigid) truck and a truck-tractor (for semitrailers) in multiple cab configurations.

[1] The current generation of the medium-duty F-Series is manufactured by Ford in its Ohio Assembly facility (Avon Lake, Ohio), replacing a joint venture with Navistar International named Blue Diamond Truck Company LLC located in General Escobedo, Mexico.

The medium-duty range retained both conventional and COE cab configurations, as a tractor, straight truck, or bus chassis.

For 1954, Ford ended production of the long-running Flathead V8, replacing it with a 239-cubic-inch Y-block V8; the 215-cubic-inch inline-six was expanded to 223 cubic inches.

[5] The front fascia was derived largely from the fourth-generation heavy-duty F-Series, adopting a full-width grille between the headlamps.

The model range was carried over from the previous generation, with the F-600, F-700, and F-800; the B-Series denoted cowled bus chassis.

Shifting from the rectangular grille of the F-Series and Ranger to the trapezoidal grille of the L-Series conventional and CL-Series COE, the sixth-generation medium-duty F-Series trucks adopted a taller, narrower hoodline, requiring the return of separate fenders (for the first time since the 1957 "Big Job" trucks).

In place of adding an extra "0" to the model designation, versions with the New Holland engines wore "Diesel" badging.

In 1992, Ford introduced Cummins 5.9 L B-series and 8.3 L C-series straight-six diesels, phased in to replace the Ford–New Holland engines.

Following the sale of the Aeromax/Louisville and Cargo heavy-truck ranges to Freightliner in 1997, these became the largest vehicles produced by Ford in North America.

Following the 1999 split of the F-Series into light- and heavy-duty vehicles, medium-duty trucks became part of the Super Duty range.

Again produced with separate fenders, the only visible exterior parts shared with the previous generation were the headlight/turn signal clusters.

The 6.0L Power Stroke replaced the aging (and no longer compliant with California noise regulations) 7.3L for the 2004 model year.

The 6.8L 30-valve Triton V10 produces 362 horsepower (270 kW) and 457 foot-pounds force (620 N⋅m) of torque and is mated to the TTC Spicer ES56-7B seven-speed manual.

[13] Following the 2015 dissolution of the Blue Diamond Truck joint venture, Ford shifted medium-duty truck production from Mexico to its Avon Lake, Ohio assembly plant, alongside E-Series cutaway van chassis and F-53/F-59 motorhome/commercial stripped chassis.

[13] Sharing the cab with the previous generation, the eighth generation abandons the shared Blue Diamond chassis for an all-new chassis developed by Ford; the carryover cab design was largely chosen to accommodate the needs of body manufacturers.

The 6.8L Triton V10 gasoline engine made its return, with an option for conversion to propane or compressed natural gas (CNG).

The fenders and hoodline are revised slightly; the standard mesh grille abandons the three-slot configuration, centering the Ford Blue Oval emblem alone.