The $US50,000 ($A75,221) award was established four years ago by bookstore owner-philanthropist Bradley Tusk and political strategist Howard Wolfson.
"Crook Manifesto is a portrait of a man, but also his city," Whitehead, a native New Yorker, said in a statement.
"Capturing the dynamism of my hometown and its crazy citizens is at the heart of the project, so I can't express how lovely it is for the book to be recognised by the Gotham Book Prize."
In a joint statement, Tusk and Wolfson praised Whitehead's novel as the kind of book they had hoped to celebrate, one that captures "the city in all of its complexity."
Previous winners of the Gotham Prize include Andrea Elliott's non-fiction book, Invisible Child and the James McBride novel Deacon King Kong.
Whitehead is among America's most celebrated authors, a two-time Pulitzer Prize winner whose works include The Underground Railroad and The Nickel Boys.
He has called Crook Manifesto the second book of a planned Harlem trilogy, which began in 2021 with Harlem Shuffle.
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