In a stunning final between the world's top two players, world number one Littler came out on top after a remarkable battle against old foe Humphries to claim an 11-10 victory and secure the £350,000 top prize in front of a packed crowd in the capital.
The reigning world champion averaged a remarkable 111.67 and hit 12 maximums, while Humphries averaged 105.60 in a final that oozed quality.
Humphries, bidding to retain the title he won last year, produced a superb display of finishing throughout much of the contest and repeatedly punished Littler's missed doubles to stay alive.
The defending champion took an early 2-0 lead before Littler settled into the match, reeling off three straight legs to move ahead at 3-2.
The quality then rapidly escalated as Humphries landed a brilliant 134 checkout before a clinical 121 bull finish helped him surge into a 6-3 advantage, with both players averaging comfortably above 110 at the interval.
Littler responded in spectacular fashion. The teenager clawed his way back into the contest with a string of huge checkouts and relentless scoring, including an 11-dart leg finished with an 84 checkout to level at 7-7.
With the pressure mounting, the final swung dramatically from one player to the other.
Humphries looked poised to retain his crown after moving 9-8 ahead, but Littler replied immediately with a composed 56 checkout before threatening a nine-darter in the next leg after opening with two maximums and seven perfect darts.
That leg moved Littler 10-9 ahead and within touching distance of the title, yet Humphries refused to go away.
Premier League recap: Littler beats Humphries in final to regain title
After Littler missed a match dart, Humphries pinned double four to force sudden death and seize the throw advantage for the deciding leg.
The momentum briefly appeared to be with Cool Hand, but a trebleless visit at the worst possible moment opened the door once more.
Littler capitalised ruthlessly, eventually mopping up 54 to clinch the Premier League crown and complete another landmark night in his extraordinary rise.
Emotional Littler
"It was a rollercoaster first four weeks, bottom of the table, but then the fifth night I won my first night," Littler told Sky Sports immediately after the victory, sharing a hug with his opponent on stage.
"I had to pick myself up after some tough times. I think I had a 79 average in Brighton, or something like that, and it was tough. But I am here with the trophy.
"After Brighton and the incident in Manchester, I was sat at home saying to Faith (his girlfriend): 'I don't want to do it anymore, just the crowd every week'. I said to her: 'I'm down bad'."
"If I lost, no one would have found out what I said on stage," Littler added afterwards in his press conference.
"But I felt I had to get it out there. I hope it's a turning point. I'm not asking for sympathy; I told the world how I was feeling about the Premier League.
"After the Brighton game and the Manchester game, I feel I proved everyone wrong again.
"It's been tough; it took me six weeks to win a night. I was playing OK, but nowhere near my best. But I picked up momentum."
Price and Clayton go to the wire
Humphries had looked in superb form throughout the evening. The world No. 2 - who had struggled for form initially but found his rhythm at a pivotal moment in the season - defeated Jonny Clayton 10-9 in a tense semi-final marred by whistling in the crowd.
The Ferret had threatened to pull clear after reeling off several legs in succession, but Humphries held his nerve in sudden death to reach the final.
Littler's route to the title was equally dramatic.
The teenager overcame Gerwyn Price 10-9 in a fiery semi-final that saw the Welshman roar back from 9-4 down to force a deciding leg. Littler missed six match darts and had to endure some colourful on-stage antics before eventually pinning double 16 to narrowly escape with victory.
Littler entered Finals Night having already secured top spot in the league phase for a third consecutive season after six nightly wins across the campaign.
Humphries, meanwhile, was attempting to join Phil Taylor and Michael van Gerwen as only the third player to retain the Premier League crown. Instead, the night belonged to Littler once again.
Already the world champion and the dominant force throughout the league campaign, the 19-year-old added another major televised title to his rapidly growing collection with one of the finest performances of his career.
The pair will now focus on reuniting as England's entrants for the upcoming World Cup of Darts.
Premier League Finals Night results
Semi-finals
Luke Littler 10-9 Gerwyn Price
Luke Humphries 10-9 Jonny Clayton
Final