The victory made Humphries the first player to win the tournament in consecutive years, as he overcame the world No. 1 in another high-quality chapter of their growing rivalry.
Humphries made the stronger start, racing into a 4-1 lead, before Littler responded with four straight legs to move in front.
Humphries, however, halted the momentum by levelling at 5-5 before producing an 11-dart decider to seal an 8-7 victory with a 104 average.
“This is the most iconic venue I think darts will ever go to,” Humphries said after lifting his third World Series title.
“Every year we come here, it gets better and better, and the fans have been absolutely amazing. It’s been insane.
“It’s great to go back-to-back. I’m always out to set records and do things that not many players have done.
“Me and Luke always have fantastic games, and it’s just another brilliant game in the saga of Luke v Luke.
“I feel if I can keep performing like this, then I can keep pushing him, because he’s unbelievable. He’s the toughest player in the world to beat.”
Humphries had earlier come through a pair of testing matches to reach the final. He beat Stephen Bunting before recovering from 6-3 down against Gian van Veen, surviving two match darts on the way.
Littler booked his spot in his first US Darts Masters final with victories over Jim Long and James Wade. The 19-year-old hit nine 180s in the final and looked set to complete the turnaround before Humphries found another gear in the closing stages.
“It was an unbelievable experience,” Littler said after the final.
“There were a lot of England fans here who are going to the (FIFA World Cup) game, so I appreciate them coming along.
“As the night went on, they got louder and louder, and I wish I was in the crowd with them to be fair.”
Earlier, Wade defeated Gerwyn Price to reach the semi-finals, while Van Veen averaged more than 106 in a 6-3 win over Jonny Clayton.
Results
Quarter-finals
Luke Littler 6-1 Jim Long
James Wade 6-3 Gerwyn Price
Luke Humphries 6-3 Stephen Bunting
Gian van Veen 6-3 Jonny Clayton
Semi-finals
Luke Littler 7-4 James Wade
Luke Humphries 7-6 Gian van Veen
Final
Luke Humphries 8-7 Luke Littler