The Panthers led 24-4 early in the second half in Townsville on Saturday night and the Cowboys displayed guts and skill to cut the lead to just four at one stage.
The visitors and defending three-peat premiers set up the victory on the back of repelling the Cowboys on multiple occasions in the opening half. They did it again at the death after the hosts stormed home to almost clinch it.
Nathan Cleary, rusty in his return from a month's absence with a hamstring injury, stopped centre Valentine Holmes with a desperate effort in the final seconds.
Panthers winger Brian To'o, in his 100th NRL game, was enormous on his way to 17 tackle busts, a try and running for 194m.
Fullback Dylan Edwards, another star for the Panthers, saved a try on rampaging Cowboys second-rower Jeremiah Nanai, then scored one at the other end with two crucial plays in the first half.
Cowboys winger Semi Valemei dropped a Cleary bomb after the break, Liam Martin swooped to score and the Panthers went out to 24-4.
The Cowboys weren't done, however. Holmes crashed over from a scrum move in the 49th minute. Fullback Scott Drinkwater then put charging back-rower Kulikefu Finefeuiaki in for a try, before half Chad Townsend unleashed rampaging Nanai to score next to the sticks.
A 20-point lead was cut to four in the space of 12 minutes, but the Panthers found another gear at the end despite making 320 tackles to 268.
To'o scored a cracker in the corner after a floating Jarome Luai cut-out pass in just the third minute.
Penrith finished the first half with an intercept try to Paul Alamoti, who swooped on an errant Drinkwater pass.
Alamoti was a late call-up after regular winger Sunia Turuva had been ruled out with a suspected knee injury.
Alamoti had his best ever game in the NRL, running for an extraordinary 241m.
The Panthers were also without forwards Moses Leota (shoulder) and Scott Sorensen (knee), but found a way to win and stay in the top four.