Phoenix and Mara lead an A-list cast in "Don't Worry, He Won't Get Far on Foot", US director Gus Van Sant's latest feature.
It is based on a memoir by John Callaham about his experience turning to art after a car accident left him paralysed.
The 68th annual Berlinale, Europe's first major cinema showcase of the year, will also feature the world premiere of "Eva" by French filmmaker Benoit Jacquot, starring Huppert as a femme fatale who wreaks havoc in the life of a prominent writer.
German actress Sandra Hueller, who starred in global art-house hit "Toni Erdmann", leads the cast of Berlin contender "In den Gaengen" by director Thomas Stuber.
The February 15-25 festival also announced Russian competition entry "Dovlatov" by Alexy German Jr, Laura Bispuri's "Daughter of Mine" from Italy, Germany's "Mein Bruder heisst Robert und ist ein Idiot" by Philip Groening, and Polish director Malgorzata Szumowska's "Mug" for its line-up.
The event had previously announced it would open with the world premiere of US filmmaker Wes Anderson's "Isle of Dogs", an animated feature voiced by stars including Bill Murray, Jeff Goldblum, Scarlett Johansson, Greta Gerwig and Frances McDormand.
It will be Anderson's fourth turn in competition at the Berlinale following "The Royal Tenenbaums", "The Life Aquatic with Steve Zissou", and "The Grand Budapest Hotel", which kicked off the festival in 2014.
In 2017 Hungary's "On Body and Soul", a tender love story set in a slaughterhouse, won the Golden Bear and has now been short-listed for a best foreign language film Oscar.