In his first role since wrapping on Shameless, Threlfall will play Detective Inspector Len Harper in the four-part thriller.
Russell Tovey (Being Human), Steven Mackintosh (Criminal Justice) and David Bamber (The King's Speech) will also appear in the serial, written by Inside Men's Tony Basgallop.
Victoria Hamilton (Lark Rise To Candleford), Indira Varma (Luther) and Claudie Blakely (The Night Watch) make up the rest of the cast.
Described as a "thrilling state-of-the-nation whodunnit", What Remains will see a young couple - played by Tovey and Amber Rose Revah - uncover the corpse of Melissa Young (Jessica Gunning) hidden in their new flat.
The discovery leads to a murder investigation led by Threlfall's Harper and has serious ramifications for each of Melissa's neighbours, who each had a connection to the victim.
"The key to writing and casting What Remains has been in ensuring that we had the right chemistry between the characters," said writer Basgallop. "Fortunately we've landed a cast with the quality and experience to pull the audience in any direction we choose to take them."
What Remains is currently filming in London.
> Spooks, Scott & Bailey creators for new BBC One shows
> Merlin star Colin Morgan joins Gabriel Byrne in BBC drama Quirke