The star will join returning cast members Martin Compston, Vicky McClure and Adrian Dunbar on the show when she takes on the role of DCI Roz Huntley.
The character is described as the police anti-corruption squad's "most devious opponent yet".
Newton said she "couldn't be more thrilled" to join the show, which begins filming in Belfast next month.
"I watched the last three seasons of Line of Duty with breathless admiration for its creators, both behind and in front of the camera," she said.
Co-star Compston added: "It's a testament to how well Line of Duty has done [in the] last few years that we can attract someone of Thandie Newton's calibre to the show. It's great to have her on board."
Newton shot to international stardom after appearing in 2000 film Mission: Impossible II and went on to star in films including The Chronicles of Riddick, 2012 and the Oscar-winning film Crash.
She also appeared on the small screen in ER, The Slap and US drama Rogue - and will next be seen in the upcoming TV adaptation of Westworld, based on the 1973 sci-fi film written by Michael Crichton.
The actress follows in the footsteps of Lennie James, Keeley Hawes and Daniel Mays, who have guest-starred as the lead character in Line of Duty for the past three series.
Bafta winner Jason Watkins, Lee Ingleby and Royce Pierreson will also appear in series four, which will move to BBC One after its ratings success on BBC Two - becoming the highest-rating drama series ever on the channel.
Creator and writer Jed Mercurio teased he was looking forward to "tormenting the nation with ever more diabolical plot twists".
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Actress Thandie Newton is to star as the guest lead character in the next series of hit BBC drama Line of Duty.