The pair were meeting in their third ranking final of the season, with Humphries winning both previous tussles to claim European Tour titles in Prague and Stuttgart.
However, Cross avoided the unwanted hat-trick by winning seven of the last eight legs to complete a comprehensive victory, denying Humphries his sixth ranking title of the campaign.
Following four straight holds to kick off Friday's final, Cross struck the first blow with a 12-dart break in leg five, cementing that advantage to establish a two-leg buffer.
The 31-year-old then produced a sublime 123 checkout on the bull to stretch his lead to 6-3, and after converting a two-dart 76 kill to move to the brink of victory, he sealed the deal with a 15-darter via double ten.
"I'm enjoying my darts again," said Cross, who averaged 98.87 in Friday's showpiece to claim the £12,000 winner's prize.
"This week my form had been disastrous, but I turned up today and got the win, which takes a little bit of pressure off.
"These are great tournaments to win. Every player is capable of hitting 100+ averages, but getting back on that stage from September onwards, that's where I want to be.
"That is where I belong, and I love it. My only goal is to win, nothing more, nothing less."
Cross produced his best performance of the day in the semi-finals, averaging 109.49 to overcome Chris Dobey 7-4 in a spectacular showdown.
The 2018 World Champion was the epitome of consistency in Barnsley, easing past Karel Sedlacek and David Evans earlier in the day, before edging out UK Open semi-finalist Keane Barry in a last-leg shoot-out.
Cross then swept aside Mickey Mansell to seal his spot in the last eight, where he defeated Jose De Sousa - avenging his defeat against the Portuguese star at last month's World Matchplay.
Humphries was unable to secure his second Players Championship crown of 2022, despite firing in four ton-plus averages, including a sensational 111.14 in his semi-final success against Martin Schindler.
The Newbury ace also posted a stunning 108.65 average to whitewash Luc Peters, after recording battling victories over American duo Danny Baggish and Jules van Dongen.
Humphries then defied ton-plus averages from Matt Campbell and Dimitri Van den Bergh to seal his place in the semi-finals, where he rattled in four successive 12-darters to stun Schindler.
"Credit to Rob, he deserves a title with the way he's been playing this year," said Humphries, who continues to close in on a place in the world's top ten.
"In the quarter-finals and semi-finals today I pulled it out of the bag, I played really well, and I felt really good in the final, they just weren't dropping in."
German number two Schindler was featuring in his second ProTour semi-final in as many months, defeating veteran duo Steve Beaton and Simon Whitlock en route to the last four.
Two-time ProTour winner Dobey also impressed at the Barnsley Metrodome, posting two ton-plus averages and dumping out Mensur Suljovic before succumbing to an inspired Cross.
Elsewhere, Jack Main remarkably landed his second nine-darter in as many days, achieving perfection during his second round victory over Niels Zonneveld.
2022 Players Championship 24
Friday August 5, Barnsley Metrodome
Luke Humphries 6-3 Matt Campbell
Dimitri Van den Bergh 6-2 Ross Smith
Madars Razma 6-3 Dirk van Duijvenbode
Martin Schindler 6-2 Simon Whitlock
Chris Dobey 6-3 Krzysztof Kciuk
Mensur Suljovic 6-4 Dave Chisnall
Rob Cross 6-1 Mickey Mansell
Jose De Sousa 6-1 Vincent van der Voort
Luke Humphries 6-3 Dimitri Van den Bergh
Martin Schindler 6-5 Madars Razma
Chris Dobey 6-3 Mensur Suljovic
Rob Cross 6-4 Jose De Sousa
Luke Humphries 7-3 Martin Schindler
Rob Cross 7-4 Chris Dobey
Rob Cross 8-3 Luke Humphries