Time magazine called the film "smoothly troweled and thoroughly entertaining." A. H. Weiler of The New York Times made it a "Critic's Pick" and said it was the "year's most scenic, intriguing and merriest chase"; Weiler complimented the two leads:
Cary Grant, a veteran member of the Hitchcock acting varsity, was never more at home than in this role of the advertising-man-on-the-lam. He handles the grimaces, the surprised look, the quick smile, ... and all the derring-do with professional aplomb and grace, In casting Eva Marie Saint as his romantic vis-à-vis, Mr. Hitchcock has plumbed some talents not shown by the actress heretofore. Although she is seemingly a hard, designing type, she also emerges both the sweet heroine and a glamorous charmer.
Film critic Charles Champlin saw the film as an "anthology of typical Hitchcockian situations", and was particularly taken by the scene and suspense in which Grant's character avoids death when attacked by a crop dusting plane in the cornfields, which he believed was representative of Hitchcock's finest work.
During its two-week run at Radio City Music Hall, the film grossed $404,056, setting a record in that theater's non-holiday gross.
According to MGM records the film earned $5,740,000 in the US and Canada and $4.1 million elsewhere, resulting in a profit of $837,000.
The London edition of Time Out magazine, reviewing the film nearly a half-century after its initial release, commented:
Fifty years on, you could say that Hitchcock's sleek, wry, paranoid thriller caught the zeitgeist perfectly: Cold War shadiness, secret agents of power, urbane modernism, the ant-like bustle of city life, and a hint of dread behind the sharp suits of affluence. Cary Grant's Roger Thornhill, the film's sharply dressed ad exec who is sucked into a vortex of mistaken identity, certainly wouldn't be out of place in Mad Men. But there's nothing dated about this perfect storm of talent, from Hitchcock and Grant to writer Ernest Lehman (Sweet Smell of Success), co-stars James Mason and Eva Marie Saint, composer Bernard Herrmann and even designer Saul Bass, whose opening-credits sequence still manages to send a shiver down the spine.
Author and journalist Nick Clooney praised Lehman's original story and sophisticated dialogue, calling the film "certainly Alfred Hitchcock's most stylish thriller, if not his best".
North by Northwest currently holds a 100% approval rating on the review aggregator Rotten Tomatoes, based on 61 reviews. The site's consensus calls the film "Gripping, suspenseful and visually iconic" and claims it "laid the groundwork for countless action thrillers to follow".
The film ranks at number 98 in Empire magazine's list of the 500 Greatest Films of All Time. The Writers Guild of America ranked the screenplay No. 21 on its list of 101 Greatest Screenplays ever written. It is ranked the 40th greatest American film by the American Film Institute.