Of the Panthers' NSW quintet, only Isaah Yeo backed up for their second loss in as many games when fit Origin players have been rested or unavailable this season.
All-conquering Penrith have traditionally flaunted their depth during the Origin period, losing only once in the mid-year representative window across their last two premiership seasons.
But at home on Sunday, execution issues meant the Panthers could not make the most of ample opportunities in wet conditions.
"It felt like we were building towards something but it was like baking a cake and having no icing," said coach Ivan Cleary.
"(Origin absences) are definitely part of it.
"(But) it's not about the Origin players, it's about who played."
The Cowboys were made to contend with the absence of all six of their own Origin players, two sin-binnings and a flood of Penrith possession that bordered on biblical in the first half.
But when 18-year-old Jaxon Purdue slid over midway through the second half, the Cowboys were on their way to a fourth consecutive away win and first victory in Penrith since 2016.
"Over the course of my time here at the the club, it's probably (one of) the more mature performance we've put in," said Cowboys coach Todd Payten.
Penrith had 39 tackles in the red zone and eight penalties before halftime, but only one try to show for it, as replacement halves Jack Cole and Brad Schneider struggled to generate points.
"The connection wasn't quite there tonight, particularly the way we finished off our sets," Cleary said.
"If you're not really taking opportunities at the right time, that's a part of that."
The Cowboys had no such issues to begin the game, clicking into gear after Paul Alamoti sprayed the opening kick-off out on the full.
Kyle Feldt grabbed a looping cut-out pass from fellow veteran Chad Townsend and burst through Alamoti, shifted to the wing, for first points after nine minutes.
Kyle Feldt opened the Cowboys' scoring in their upset win over the Panthers. (James Gourley/AAP PHOTOS)
Attacking wide continued to work for the Cowboys, who made it 12-0 through Braidon Burns shortly after losing Scott Drinkwater to the sin-bin following repeated set restarts.
At one point late in the second half, the Panthers enjoyed 11 of 12 sets in a row and it took Schneider skipping past a tiring Drinkwater to score their only try of the night.
It came just after Purdue went to the sin-bin for tripping Daine Laurie, an act that is likely to land him on the match review committee's charge sheet.
Stand-in fullback Laurie looked likeliest for the Panthers with 228 run metres and James Fisher-Harris pitched in a tenacious 67-minute effort.
But Penrith were left to rue missing chances in the first half when opportunities dried up in the second.
In a hot-and-cold season, the Cowboys' win ensures they will finish the weekend inside the top eight.
Payten felt the playing group was finally beginning to gel with changes made to the club's defensive systems over the summer.
"I thought the group would get their heads around it a bit quicker than they did," he said.
"Now our attack is putting less pressure on our defence.
"We've got an abundance of skill, we've just got to pick and choose the right time to play it. That's the challenge for us."
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