Humphries had earlier swept Stephen Bunting aside 6-0 before producing a superb comeback to beat Littler 6-3 in the semi-finals, recovering from 3-0 down to end a three-match losing run against the world No. 1.
He then completed the job against Price in the final, opening up a 4-1 lead before surviving a Welsh fightback.
Price reduced the deficit to 4-4 after taking out 130 and punishing missed doubles from Humphries, but Cool Hand regained control with a hold on double eight before sealing the title after Price missed the bull for a 170 checkout that would have forced a deciding leg.
Humphries was visibly emotional after securing his return to London, admitting it would have "hurt" had he failed to defend his title at The O2.
"I'm incredibly proud of myself, probably the most proud I’ve ever been in my life," Humphries told Sky Sports.
"For the last few weeks, there has been a lot of pressure on my shoulders. To make three finals and win one means a lot."
Littler sweeps Clayton
Littler had earlier secured top spot in the league phase with a ruthless 6-0 win over Clayton, producing a statement display against the man who had been his closest challenger.
The teenager was then beaten by Humphries in the semi-finals, while Price reached the final with victories over Michael van Gerwen and Gian van Veen.
Van Veen kept his play-off hopes alive at the start of the night with a 6-3 win over Josh Rock, but Humphries' victory in the final confirmed the top four with one week of the league phase still to play.
Premier League Night 15 results
Quarter-finals
Gian van Veen 6-3 Josh Rock
Gerwyn Price 6-4 Michael van Gerwen
Luke Humphries 6-0 Stephen Bunting
Luke Littler 6-0 Jonny Clayton
Semi-finals
Gerwyn Price 6-4 Gian van Veen
Luke Humphries 6-3 Luke Littler
Final
Luke Humphries 6-4 Gerwyn Price