Huge region over in USA is Appalachia (4)
I believe the answer is:
asia
'huge region' is the definition.
(I've seen this before)
'over in usa is appalachia' is the wordplay.
'over' says the letters should be written backwards.
'in' indicates a hidden word.
'aisa' is hidden within 'usa is appalachia'.
'aisa' written backwards gives 'ASIA'.
(Other definitions for asia that I've seen before include "Thailand and its location" , "The Orient" , "One-third of all land" , "group of countries" , "Continent of the Hindu Kush" .)