The reigning Wally Lewis Medallist 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.
Dearden will undergo surgery next week and is guaranteed to be sidelined from 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 the third game of the series, to be contested in Brisbane on July 8.
Dearden inspired Queensland to come from behind for a 2-1 series win after replacing captain Daly Cherry-Evans as halfback for game two last series.
The Cowboys co-captain, prized for his electric running game, was awarded the Wally Lewis Medal as player of the series.
His form has been less consistent for the Cowboys this season, but Dearden had been considered a walk-up starter for game one.
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 at Origin level in recent years.
A 26-time Origin veteran, Cherry-Evans said earlier this year that he would always remain open to an Origin 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.
Munster, Val Holmes, Tino Fa'asuamaleaui, Trent Loiero, Gehamat Shibasaki and Harry Grant are among incumbent Queensland players to battle form concerns in 2026.
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 after the tackle midway through the second half 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 the Eels.
The Cowboys have confirmed back-up hooker Soni Luke will also miss a month with a knee injury suffered in the loss to Parramatta.
12°C