Malkovich was born in Christopher, Illinois, and grew up in Benton, Illinois. His father, Daniel Leon Malkovich, was a state conservation director and publisher of Outdoor Illinois, a conservation magazine. His mother, Joe Anne, owned the Benton Evening News, as well as Outdoor Illinois.
In 1976, Malkovich, along with Joan Allen, Gary Sinise, and Glenne Headly, became a charter member of the Steppenwolf Theatre Company in Chicago. He moved to New York City in 1980 to appear in a Steppenwolf production of the Sam Shepard play True West for which he won an Obie Award.
In early 1982, he appeared in A Streetcar Named Desire with Chicago's Wisdom Bridge Theatre. Malkovich then directed a Steppenwolf co-production, the 1984 revival of Lanford Wilson's Balm in Gilead, for which he received a second Obie Award and a Drama Desk Award. His Broadway debut that year was as Biff in Death of a Salesman alongside Dustin Hoffman as Willy. Malkovich won an Emmy Award for this role when the play was adapted for television by CBS in 1985.
He made his feature film debut in 1984 as Sally Field's blind boarder Mr. Will in Places in the Heart. For his portrayal of Mr. Will, Malkovich received his first Academy Award nomination for Best Supporting Actor. He also portrayed Al Rockoff in The Killing Fields.
He continued to have steady work in films such as Empire of the Sun, directed by Steven Spielberg, and the 1987 film adaptation of Tennessee Williams's The Glass Menagerie with Paul Newman and Joanne Woodward.
Malkovich starred in the 1992 film adaptation of John Steinbeck's award-winning novella Of Mice and Men as Lennie alongside Gary Sinise as George. In 1994, he was nominated for another Oscar, in the same category, for In the Line of Fire. Though he played the title role in the Charlie Kaufman-penned Being John Malkovich, he played a slight variation of himself, as indicated by the character's middle name of "Horatio".
Malkovich then took a hard turn into sci-fi, playing Humma Kavula in the long-awaited film adaptation of Douglas Adams' classic novel "The Hitchhiker's Guide to the Galaxy" (2005), and then veering over to dark comedy, playing a pompous, often drunk CIA analyst who finds himself entangled in a hare-brained extortion scheme in the Coen Brothers highly divisive "Burn After Reading" (2008).
He clearly had a good time playing a senile former spy in the action comedy "RED" (2010), so much so that he returned for the sequel, "RED 2" (2013), but not before playing around with some giant robots in "Transformers: Dark of the Moon" (2011). After taking a supporting role as a mild-mannered man trying to survive a very convoluted apocalyptic event in the surprise Netflix horror hit "Bird Box" (2018), Malkovich could most recently be seen playing legendary detective Hercule Poirot in a miniseries adaptation of Agatha Christie's "The A.B.C. Murders" (BBC, 2019), as well as in another Netflix horror offering, "Velvet Buzzsaw" (2019), this time set in the art world of Los Angeles.