Welshman Clayton defied an early storm from Littler to notch back-to-back nightly wins and his fourth of the campaign.
Littler, meanwhile, was booed throughout the night following his spat with Dutchman Gian van Veen in Manchester two weeks ago.
Yet the teenager made a quick start in the final with an 11-darter and a break of throw to open a 2-0 lead.
Clayton, though, surged back by taking the next three legs to move ahead for the first time in the match.
'The Ferret' continued to pounce on some wayward finishing from Littler, eventually closing out victory despite a 92.92 average.
"I watched last week's game against Michael (van Gerwen) and it hurt a little bit when someone said I was favourite to finish bottom," Clayton told Sky Sports.
"That really hurt. It annoyed me a bit, to be honest. It's going good for myself now and I've got a massive smile on my face."
Clayton, who is now five points clear of second-placed Littler in the table, opened his night with a comprehensive 6-2 win over home hope Michael van Gerwen.
He then had to battle past Josh Rock 6-5 in an edgy semi-final contest to set up a final clash between the Premier League's top two.
Littler reaching the final boosted his hopes of qualifying for the play-offs in London, but he had to battle a hostile Rotterdam crowd from the start.
'The Nuke' walked out to strong jeers against Gerwyn Price, but was in the zone by sealing a 6-3 win to dampen down the atmosphere.
Littler then squeezed past defending champion Luke Humphries 6-5 after nearly letting a 5-2 advantage slip.
Humphries had earlier beaten Van Veen 6-2, meaning both Dutchmen in this year's Premier League were dumped out at Rotterdam's first hurdle.
The other quarter-final saw Stephen Bunting beaten 6-1 by Northern Ireland's Rock, who is currently bottom of the Premier League table.
The Premier League heads to Liverpool next week for Night 12.