After being sidelined for the past three weeks through a concussion and then calf issues, Reynolds had been hoping to return for the Broncos against Melbourne on Thursday night.
But Broncos staff advised the 36-year-old against coming back on Monday, concerned he could be underdone after limited training in recent weeks.
It means Reynolds has now played his 323rd and final game in the NRL, bowing out with premierships at South Sydney and Brisbane.
"All NRL careers come to an end and unfortunately mine is today. I won't be playing this week or next week," Reynolds said on Triple M.
"The left calf was giving me nerve issues, and then I had a little grade-one strain in the right calf which has not bounced back as quickly as I would've liked.
"I trained today and thought I would be a chance to play one last home game ... but it's not to be.
"I felt pretty good ... but I had some conversations with (coach Michael Maguire) and the medical staff and they were quite concerned with the limited training I've done.
"You want to play the game forever. But the reality is you get old, you get brittle, and you get sore, and at the end of the day you can't keep competing forever."
Confusion had surrounded Reynolds' calf for the past fortnight, with Maguire at one point telling News Corp that Reynolds was unable to train.
The Broncos halfback then spoke at a function hours later where he insisted he felt fine, before being spotted training the next day.
But Reynolds suffered his final calf blow soon after that, and it has now proved the final injury of his career.
A South Sydney junior, Reynolds made an immediate mark on the NRL with his local club when he guided them into the finals as a rookie half in 2012.
He took Souths to the promised land with their first premiership in 43 years in 2014, before also helping lead them to the 2021 grand final.
That finals charge came despite the Rabbitohs being unwilling to offer him a long-term deal, and the grand final loss to Penrith marked his final game for South Sydney.
Another losing grand final came at Brisbane in 2023, before his heroics in the 2025 preliminary-final win over the Panthers helped him and the Broncos to last year's drought-breaking title.
But his final year has been a frustrating one, limited to just 14 games through persistent injuries as the Broncos crashed out of finals contention.
"I've had a great career," Reynolds said.
"I'm extremely fortunate I get to carry some great memories moving forward.
"I certainly don't regret going on this year. I'm content and happy with everything I've done in the game."
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