Yes, it will fit. It's an awesome engine!
Fordman75 has a 66 Falcon XR with one, although he hasn't completed it.
The 240/300 Big Six has 4.48" bore spacings, not 4.08" like the 144-250 sixes, so its 2 inches up on length for a start on your 221 or 250. The XY six cylinder trans wont fit, as its a f our bolt bell, and the Big Six is six bolt SBF Windsor/Cleveland at the back.
There are three ingredients to a so-called engine mount...frame mounts, rubber insulator, and the steel motor mounts. The back trans mount will follow the FMX/AOD/ C4 or C6 auto, Mazda Truck, Toploader, US Single Rail or T18 gearboxes they ran. Basically, the XY trans mount will be okay as it is.
The 240/300 engine is only fractionally longer than the 460, and is able to fit with some custom mounts. The Bronco/F150/250 run a rear mount sump, and there are some issues with the oil filter and 10 inch deck height of the engine, but it will fit. The Big Six was a 1965 invention, and never saw duty on any unibody X-series cars,
only full chassis trucks (1965 till 1996)
Broncos, (from about 1967 to 1996)
Ecconolines, (65 to 96)
Galaxies, ( same as our Aussie 390 FE's, 65 to the name change to LTD)
LTD's (till 1972)
Another person is Thad, who has a later serpentine belt drive on his early Ranchero (1963 Falcon ute).
The 300 engine frame mounts on trucks were the same as the Aussie 250/302/351. The 300 got a special engine mount so it required no mods to fit it. Ford made everything so simple to swap between the SBF and 240/300's.
It's likely you'll have to modify the 250 XY frame mount to suit the existing Engine mounts and rubber insulators, rework the pan, and go for a new Cleveland style pick-up to the oil pump.
If you use the 1987 on EFI 4.9 serpentine drive, you can save some extra space. The pre XD Falcons had massive amounts of space in front of the radiator, so there won't be any problems.
If you want to make some money, get a mint carb engine on import, and then get someone to make special engine mounts.
Sorry, I've slobbered a bib full. Check out the Bronco/F series Big Six Forum. The guys are really knowledgable, and just remember, the 300 is Fords best kept racing secrete!!!!