The Romeo + Juliet star will play Del in the pilot, according to Deadline.
Like the original series, ABC's Only Fools will follow Del, his brother Rodney and their grandfather as they devise get-rich-quick schemes in their quest to become millionaires.
Derek 'Del Boy' Trotter was famously played by David Jason in the BBC version, which ran from 1981 to 2003.
Leguizamo is best known for his film credits, including roles in 1993's Carlito's Way, 2001's Moulin Rouge! and last year's The Lincoln Lawyer.
His past television work includes a 12-episode stint on ER and a starring role on Spike TV's The Kill Point.
David Jason recently suggested that the remake will struggle, arguing that the show's concept won't "travel across the pond".
"They can do brilliant comedy [in America] but I don't see that they can bring off Fools and Horses," he said. "It might work but you've got to change it so much that, in the change, in order to Americanise it, do you lose the whole concept of the piece?"
Happy Endings writers Steven Cragg and Brian Bradley have adapted Only Fools and Horses for US television and will executive produce alongside Leguizamo's manager Jeff Golenberg.
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