Scans showed Englishman Thompson had two breaks in his ankle after going down in training on Tuesday.
He'll see a specialist on Wednesday, but Bulldogs football boss Phil Gould confirmed he would be facing a significant stint on the sidelines.
"Unfortunately Luke Thompson's injury is quite serious. Prognosis is for minimum six months recovery. Possibly longer depending on surgery type," Gould wrote on Twitter.
"Very sad for Luke and the club. Thunderbolts happen."
Thompson joins fellow forward Tevita Pangai Jr in the casualty ward, the Tonga prop looking at a month out of action with a calf injury.
The Bulldogs named Max King and Ryan Sutton in the front row for Saturday's clash with Manly, the latter in line for his club debut after switching from Canberra this off-season.
Hulking youngster Franklin Pele has been named on the bench, with fellow prop Jayden Tanner added in place of Thompson.
Tanner is one of three NRL debutants named for the Bulldogs this weekend along with second-rower Jacob Preston and centre Paul Alamoti.
Thompson only played 13 games in 2022, suffering a serious concussion before taking extended leave to be with his sick mother in England.
He impressed for his national team over the NRL off-season, part of the England side that reached a World Cup semi-final before falling to Samoa.
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