Ralph Bakshi had made a previous attempt to direct the film, a production he was to co-produce with Steve Krantz and author Hubert Selby Jr. Actor Robert De Niro accepted a major role in the film. However, the project fell apart when Bakshi and Krantz had a falling out. Bakshi and Selby became friends, and, according to Bakshi, they "tried a few other screenplays after that on other subjects, but I could not shake Last Exit from my mind."
This movie's opening prologue is a quotation from the bible. It reads: "I will rise now, and go about the city in the streets, and in the broad ways I will seek him whom my soul loveth. Song of Solomon 3:2:2".
Patricia Arquette, who was originally cast in the lead role of Tralala, dropped out before the filming started when she discovered she was pregnant. in 2015, while a guest on "Fresh Air with Terry Gross," Arquette talked about why she dropped out and how difficult it was for her to make the decision to do so: "that character really goes through a lot of difficult things in that movie, and it was my first time having a baby. And I thought, I don't want to be pregnant and emotionally go through this woman's journey that's very violent at certain points with a baby inside me. And it was a very difficult moment where I sat with the producers, and they said, well, we think you could still shoot this while you're pregnant. I said, 'well, let me just walk around the block.' And I came back and I said, 'I can't do this movie 'cause I don't know how that will be for my baby.' And I didn't know if I would ever get another movie. And when I--right after I had him, I'd audition and I wasn't getting movies. And I remember walking into this restaurant on Sunset Boulevard and saying--you know, applying for a job as a waitress. And I said, 'look, I'm smart. I don't have a lot of experience. I like people, I'm nice to people, I learn fast and I have a baby to feed.' And they give me the job, and I was going to start on Wednesday. That Monday, I got a call that I got my first movie after my son."