In an absorbing final, Littler started strongly and raced into a 3-1 lead following some relentless finishing.
The 19-year-old produced a stunning 153 checkout in the first leg of the second set, before back-to-back 121s saw him take control in the early stages.
Humphries has been exceptional throughout the tournament, and the 30-year-old came back wonderfully from 3-1 down to level the score at 3-3 heading into the break.
A topsy-turvy contest ensued as Littler broke back in the seventh set after Humphries painfully missed three darts at double tops before Cool Hand levelled the contest with an 81 finish.
In a simply world-class showdown, Humphries remained composed to take out 108 to go 5-4 up in sets but floundered in the dying embers of the match as Littler ruthlessly won four legs on the bounce to add the Masters title to his impressive collection.
"I'm shattered, absolutely knackered," Littler told ITV after the victory.
"Going into the last break at 5-4, I said I have nothing left, absolutely nothing, but I just managed to dig deep. I was fully focused and managed to get the job done.
"It has been a weird week and tough at times, but this is why we battle every game and every leg, and I've come out victorious. It has been Luke and me in the first major of the year, and I'm sure it will continue.
"This is one I didn't have hold of, but now I have hold of it, and now there is only one left."
Price cruelly denied final spot by Littler
Earlier, Littler and Gerwyn Price played out an absorbing semi-final, and the latter was left kicking himself.
In a nine-set showdown that was mostly played on throw, Price finally broke Littler in the final set and crafted an opportunity to serve out the match.
The Welshman was left with 107 after 12 darts, but wired double tops before being punished by his arch nemesis on double 2.
Littler then closed out the final leg of the semi-final in true fashion with a 12 darter to continue his excellent record against Price.
While it wasn't to be for 'The Iceman' once more in another TV event, he can take courage from his performance.
Price matched the world champion across nine captivating sets by producing nine 180s, an average just shy of 100 and 34 per cent on the doubles.
That relentless treble hitting, which included 16 140-plus scores, is good enough to beat most players on tour, but Littler showed that he's just at a different level.