The production company wanted a locale that looked like an abandoned metropolitan area, but it was too costly to build. The producer drove through downtown Los Angeles one weekend and discovered there were no shoppers, so the majority of the film's exteriors were shot there on weekends.
Charlton Heston had read the original novel on an airplane coming back to California, and was very interested in a modern adaptation of the book; he was totally unaware of the fact it had already been made into a film long before - The Last Man on Earth (1964) starring Vincent Price.
In the film, the plague that causes the end of the world was unleashed by germ warfare as the result of a border war between China and Russia. In fact, China and Russia had some very serious border skirmishes during 1969 that had many world leaders concerned about the possibility of an all-out war between the Communist superpowers.
Early in the film, Neville sees a calendar dated March, 1975, then remarks that the local cinema is offering Woodstock (1970) "for the third straight year". This indicates The Omega Man (1971) is set in 1977. (Neville himself mentions the August 5, 1977 while recording his audio diary.)
The writers came up with the idea to make Neville's love interest an African-American woman. Even though an interracial relationship was still considered controversial in the seventies, the writers figured that in a world where humanity had almost become extinct, the few survivors would no longer care about such issues.
The windows through which Neville shoots at the Family member in the opening credits are still there at 840 Santee Street, Los Angeles. You can also still see the blind alley behind his car before he screeches the breaks at 743 Santee Street (the "LA Cornell Building No. 6" is still there, unchanged). Likewise, the red-brick warehouse in the background as he shoots is still there, too, at 825 S. Los Angeles Street, Los Angeles. Even the little "deluxe burgers" stand he passes right before stopping is still there (although now covered & without external signs).
Neville's primary weapon during the film is a Smith & Wesson M76 submachine gun, sometimes fitted with a flashlight. During the first night attack by the Family, Neville uses a Browning Automatic Rifle (BAR) with an infrared scope.
The façade/set used for Neville's fortress/home still stands relatively unchanged on Warner Brothers Ranch Park Boulevard (formerly Columbia Ranch) in Burbank. It can be easily seen using Google-Maps 3D. The façade faces east-southeast.
British studio Hammer Films had previously contemplated a film adaptation of Richard Matheson's book under the title of "The Night Creatures", written by Matheson himself. The project was ultimately deemed too graphic, floundered and eventually died.
The movie was the inspiration for two CBC Radio comedy series, "Steve the First" and "Steve the Second", starring Matt Watts and Mark McKinney. Each series was about a slacker (the second the son of the first), called upon to save the world after a disaster.
The street/set down which the Family walks (and across from where Lisa reveals her change into a mutant-albino) still stands relatively unchanged on the Warner Brothers Studios Burbank back-lot. It is one block north of Warner Brothers Stage 25, very close to the columned building that served as the Family's "hive" (which is still also present).