The Jackass actor has been described as the favourite for the part by directors the Farrelly brothers, according to Variety.
Speaking to the site, Bobby Farrelly said: "Knoxville is a real-life stooge. He's a real-life Moe."
They added that the film is meant to pick up from the trio's last work and is not intended to be a biopic.
Benicio Del Toro is the other contender for Moe, with the roles of Curly and Larry remaining open.