It stars Melville and Pierre Grasset as two French journalists in New York City who are searching for a missing United Nations diplomat.

The evening of December 23, Moreau, a reporter for Agence France-Presse (AFP), is asked by his editor to find out why Fèvre-Berthier, the French delegate to the United Nations, did not attend that day's meeting of the General Assembly.

They visit Judith Nelson, a stage actress, between the acts of a Broadway play at the Mercury Theater, Virginia Graham, a jazz singer, at a Capitol Records recording studio, and Bessie Reed, a burlesque dancer, at the Ridgewood Rathskeller, and even talk to Gloria, a high-end call girl who "specializes in diplomats", at a French-Chinese-themed brothel, but do not find Fèvre-Berthier.

When she begins to become hysterical and does not want to say any more, Delmas demands to know where Fèvre-Berthier is and how he died until he learns that Judith had found the diplomat dead in her apartment, presumably of a heart attack.

Although he was a lifelong Americanophile who incorporated American iconography and filmmaking tropes into his work throughout his career, Melville only shot parts of one other film, 1963's Magnet of Doom, in the United States.

[1] Two Men in Manhattan was Melville's least successful film at the box office, managing to sell just 308,524 tickets, which was less than half that of Bob le Flambeur three years earlier.

At this time, Richard Brody of The New Yorker described it as a "snappy and streetwise mystery" constructed around "a politically inspired and rigorously principled conflict pitting journalistic candor against what one character calls ‘the prestige of France.

'"[3] In The Dissolve, Scott Tobias wrote that the film "feels neither French nor American, but some beguiling combination of both," while praising its black-and-white cinematography and careful examination of the moral dilemma at its center.