At one point trailing 3-0 and 5-3 to the 18-year-old sensation, Humphries turned in a spectacular second-half display in front of 14,000 supercharged spectators to claim the trophy.
In a rematch of last year's final, which culminated in Littler's first-ever major title, Littler averaged 100 for the contest to Humphries' 97, while both players struggled on the checkouts by their usual standards, with both sticking just 30% of their finishes.
Littler threw 10 180s, Humphries landed five - all of which came after the break.
"This one means the world to me, that was the one I was missing. It was the one I wanted, I have done it now," the newly crowned Premier League champion told Sky Sports after the victory.
"If I don't win another title, I am happy as I have done the three hardest ones to do.
"Phil Taylor has given me a lot of support over the last couple of weeks, so Phil, if you are watching, thank you. He gave me a lot of advice and that extra support."
Runner-up Littler, keeping in good spirits, added: "No one likes losing, but I'm glad it's over. It's been a tough 17 weeks.
"I've set many records. Personally, I don't think they'll be broken. A little bit of a break now and then on to the world series."
Teenager Littler had topped the league table for a second consecutive year with 45 points - a new Premier League record - and collected an unprecedented six nightly wins in Glasgow, Brighton, Cardiff, Newcastle, Birmingham, and Sheffield.
Defending champion Littler was aiming to become only the third player to win back-to-back Premier League titles, joining illustrious company alongside Phil Taylor and Michael van Gerwen.
Humphries, meanwhile, was looking to add an elusive Premier League title to his sparkling trophy cabinet, and he duly delivered, albeit with neither player at their swashbuckling best.
The 30-year-old now joins an elite group of players to have captured darts' triple crown: winning the World Championship, World Match Play and the Premier League.
Close calls in the semi-finals
Earlier on in the first semi-final of the evening, Littler toppled a very game Gerwyn Price 10-7.
The Iceman started the faster of the pair, with both players breaking one another repeatedly. Littler would swiftly find himself trailing the Welshman 6-4 heading into the break.
But the Nuke would come out all guns blazing from the seventh leg onwards to douse Price's fired-up playing style.
Breathing a sigh of relief to the cameras when walking off the stage, Littler would storm through the remainder of the match, winning all but one leg and finishing with an average of 104 to Price's 95, although he struggled on the doubles with just 10 of 29 pinned.
Humphries, meanwhile, was taken to the brink by Nathan Aspinall in the second leg, narrowly avoiding an upset after struggling to keep hold of the lead against the Stockport native.
Cool Hand Luke took the first two legs before fluffing his lines on several occasions, but ultimately his 180 scoring power saw him through with a 10-7 victory to set up a rematch of last year's final, won by Littler.
Humphries receives £275,000 in prize money for the victory, with £125,000 going to Littler as runner-up and £85,000 to each of the semi-finalists.