It comes as Maroons back Valentine Holmes prepares to undergo scans on a shoulder injury suffered in St George Illawarra's loss to Newcastle on Saturday.
Dearden suffered his syndesmosis injury in North Queensland's extra-time NRL loss to Parramatta on Friday night and will miss between six and eight weeks.
The 25-year-old will undergo surgery next week and is guaranteed to be sidelined for at least the first two games of the Origin series.
If he required the full eight weeks to recover, Dearden would not play again before game three, to be contested in Brisbane on July 8.
Dearden inspired Queensland to come from behind for a 2-1 series win last year after replacing captain Daly Cherry-Evans as halfback for game two.
The Cowboys co-captain, prized for his electric running game, was awarded the Wally Lewis Medal as player of the 2025 series.
His form has been less consistent for North Queensland this season, but Dearden had been considered a walk-up starter for game one.
Kalyn Ponga, vying to play fullback for the Maroons, struggled to contain his disappointment after being told the news of Dearden's injury on Saturday.
"I feel for Tommy. I know how hard he works, how much he loves his footy, how much he loves Queensland," Ponga said after the Knights' defeat of the Dragons.
"He's going to be shattered. Queensland's going to be shattered."
Sam Walker and Ezra Mam appear replacement options for the series opener in Sydney on May 27, but both are uncapped at Origin level.
Newly-fit Ben Hunt seems another contender, but has mostly played hooker for Queensland in recent years.
A 26-time Origin veteran, Cherry-Evans said earlier this year that he would always remain open to a Maroons recall should Dearden or Cameron Munster be unavailable.
Queensland captain Munster looks set to retain the five-eighth jersey despite a poor start to the NRL season at Melbourne.
Dearden's absence is yet another blow for coach Billy Slater, who is already without stalwarts Jeremiah Nanai and Xavier Coates for the series opener.
Holmes could join Dearden on the sidelines, requiring scans on a shoulder injury despite playing until the end of St George Illawarra's 44-10 loss in Wollongong.
Interim coach Dean Young was unsure of the injury's severity after fulltime.
"It's not my concern, I've got more to worry about than Queensland's Origin team," he said following the Dragons' 13th consecutive loss.
The Cowboys confirmed Dearden suffered his injury in a try-saving tackle from Josh Addo-Carr during the second half of the Eels' 33-30 upset win.
Addo-Carr applied pressure to the back of Dearden's legs but was not penalised nor charged by the match review committee on Saturday.
Dearden appeared in significant pain, but initially played on.
He left the field ahead of extra time, watching as captain and would-be Origin rival Mitch Moses iced the game for Parramatta.
North Queensland have confirmed back-up hooker Soni Luke will also miss a month with a knee injury suffered against the Eels.
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