The .338-378 Weatherby Magnum started out as the wildcat cartridge, .338-378 Keith-Thomson Magnum during the early 1960s. Keith and Thomson are Elmer Keith and R.W. "Bob" Thomson. The 338-378 Keith-Thomson Magnum is a quarter of an inch shorter than the full length 338-378 Weatherby Magnum, this was because they thought it was better balanced with the slowest powder generally available at that time (H4831). The .338-378 Weatherby Magnum was added to the Weatherby product line in 1998.

The .338-378 Weatherby Magnum’s parent case is the .378 Weatherby Magnum. The .338-378 Weatherby Magnum is created by necking down the .378 Weatherby Magnum to 8.59 mm (.338 in) then fire forming it in the rifle chamber. The .338-378 Weatherby Magnum has a case capacity of about 8.1 g (125 gr). Bullets commercially available for the .338-378 Weatherby Magnum range from: 11.7 g (180 gr) to 19.4 g (300 gr) in the construction of; boat-tail hollow-point; boat-tail pointed soft; pointed soft point; heavy jacketed pointed soft point; partition; multi-core; truncated solid and monolithic solid.