The 61-year-old filmmaker never thought to use the tool in his version of Frankenstein, adapted from Mary Shelley's novel.
When asked if he used generative AI in his forthcoming $US120 million ($A183 million) take on the classic horror flick, Del Toro said he wasn't interested.
"AI, particularly generative AI, I am not interested, nor will I ever be interested," he said on a recent episode of NPR's Fresh Air podcast.
"I'm 61, and I hope to be able to remain uninterested in using it at all until I croak.
"The other day, somebody wrote me an email and said, 'What is your stance on AI?'
"My answer was very short. I said, 'I'd rather die.'"
After the host said they were "strong words" to use, Del Toro responded: "Man, not for me. I'm Mexican.
"But I think even when a human sings a song that has already been recorded six, seven times, they're filtering their experience, their life.
"I often think of Johnny Cash singing Hurt, the Trent Reznor song, and making it entirely his own, or Joe Cocker singing The Beatles.
"That's not a version, that's not remixing, that is filtering through alchemical pain and experience, and work of art into making it your own."
Despite not being fond of AI, del Toro did see similar connections between the technology and the story of protagonist Victor Frankenstein (played by Oscar Isaac).
Asked if AI informed the movie in any way, the director replied: "It did and it didn't.
"It didn't in the sense that my concern is not artificial intelligence but natural stupidity. I think that's what drives most of the world's worst teachers.
"But I did want to have the arrogance of Victor be similar in some ways to the tech bros, you know?
"He's kind of blind, creating something without considering the consequences, you know?
"And I think we have to take a pause and consider where we're going."
In the new version of Frankenstein, Jacob Elordi, 28, plays the Creature locked in conflict with his creator, Victor.
And del Toro imagined the movie as a family drama, as opposed to a traditional horror story.
"I've been following the creature since I was a kid," he said.
"I waited for the movie to be done in the right conditions, both creatively in terms of achieving the scope to make it different, and to make it at a scale that you could reconstruct the whole world.
"I'm in postpartum depression now that it's finished."
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