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 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.
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.
Rosalind Cash was uneasy before her love scene with Charlton Heston, saying "It feels strange to screw Moses." Whoopi Goldberg has claimed that the kiss between the characters played by Charlton Heston and Rosalind Cash was one of the first interracial kisses to appear in a movie, but in actual fact, there had been several such scenes in movies before this. These included Island in the Sun (1957), A Patch of Blue (1965), and Guess Who's Coming to Dinner (1967). There have been several instances on television long before The Omega Man too.
Charlton Heston had read the original novel on an airplane coming back to Los Angeles, 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 years before as The Last Man on Earth (1964), starring Vincent Price.