The Back to the Future star will play the grandfather of Del (John Leguizamo) and Rodney (Dustin Ybarra), according to Deadline.
Like the original UK comedy, the potential ABC series will follow the trio as they concoct get-rich-quick schemes in their attempts to become millionaires.
Happy Endings actor BJ Bales has also been cast as Trigger, who has been reinvented as a 'ghetto-talking con man' and Del and Rodney's 'perpetual enemy'.
In the BBC's Only Fools and Horses - which ran from 1981 to 2003 - the dim-witted Trigger was played by Roger Lloyd-Pack, while Del and Rodney's granddad was portrayed by Lennard Pearce, until the actor's death in 1984.
David Jason, who played Del in the original, recently suggested that the remake will struggle, arguing that the show's concept won't "travel across the pond".
Happy Endings writers Steven Cragg and Brian Bradley have adapted Only Fools and Horses for US television and will executive produce alongside Jeff Golenberg.