The Roosters were $11 outsiders ahead of Penrith's first clash at their adoptive home CommBank Stadium on Friday night.
They were missing 788 games of first-grade experience through injury or suspension - after losing more than another 1000 in the off-season - and had not beaten the Panthers in their past 10 meetings.
But what was supposed to be a procession for the NRL's champions turned instead into a tit-for-tat battle with a Roosters side who proved their season may not yet be a lost cause.
Down six points, the Panthers had one last chance to salvage a result attacking in the red zone on the last play.
But veteran winger Daniel Tupou, capping his two-try night, tackled Brian To'o into touch as he stretched out for what would have been an equalising score, and the Roosters held on.
Roosters captain Tedesco, a dual premiership player and State of Origin series-winning captain, put the victory in rarefied air.
"I feel like it's my proudest win," he said.
"No-one gave us a shot ... that's what media does and people do, they're quick to judge. It's on us as leaders to instil that belief in these young boys. We showed that belief tonight.
"We've set ourselves up with a performance like that. We have to keep building on that and keep getting better to produce more wins like that."
The Roosters had looked the better side in a tight contest and finally broke free with tries in back-to-back sets midway through the second half.
Superb in only his third game, rugby convert Mark Nawaqanitawase threw the last pass for Tupou to score, before a break down the left put Sandon Smith in.
NSW fullback Dylan Edwards went off after the second of those tries, apparently injuring his groin in pursuit of Smith as the Roosters took a 10-point lead.
"He could've kept playing but just the way the game was and what we needed at the time, we've got a fresh fullback (Daine Laurie) sitting on the bench," said Panthers coach Ivan Cleary.
Down 38-26 after taking a penalty goal with seven minutes remaining, the Panthers looked ready for a fast finish, spreading left to put Casey McLean in.
A second penalty goal made it a one-score game while Roosters forward Salesi Foketi was in the sin bin for a high shot, but Tupou's cover tackle sealed victory.
"'Tups' has saved a lot in that corner and Brian's scored a lot in that corner. It comes down to that play," said Roosters coach Trent Robinson.
Penrith had managed to overcome a shaky start to beat Cronulla in round one but never found their rhythm after their left centre Paul Alamoti swanned over for the opener inside three minutes.
The Roosters' three first-half tries all came after the Panthers' back three dropped Chad Townsend kicks, with McLean responsible for two of those knock-ons.
Penrith struggled to contain the energetic Roosters' second-phase play and missed an uncharacteristic 43 tackles, with Roosters hooker Connor Watson proving particularly evasive scoring his first double since 2021.
The 38 points were the most they have conceded in any game that Nathan Cleary has played since 2018.
"Those ones it's hard to have all the answers but I guess it's why we all love sport so much, it's the classic upset," coach Cleary said.
"Unfortunately, we're the ones that brought it to life tonight.
"We just weren't anywhere near good enough."
Next week's grand final rematch with Melbourne is set to provide a litmus test for a Panthers side still clearly adjusting to life without Jarome Luai and James Fisher-Harris.
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