The world champion needed to dig deep after being pegged back to 1-1, with 2021 winner Clayton then taking a two-leg lead in the third set.
Humphries turned the tide with a 146 checkout and then claimed the next two legs to open up a lead he did not relinquish, securing victory in a fourth-leg decider.
The world number one will now face Ryan Joyce in the last four after the Newcastle thrower edged out fourth seed Rob Cross 3-2.
Mike De Decker coasted into his first major semi-final with a 3-0 victory over James Wade.
The 28-year-old held his nerve to take the first set, in which he averaged 102, with a checkout of 66 in the fifth leg before doubling his advantage with a brilliant 122 in the deciding leg of the second.
The third set also went the distance, and in favour of De Decker, as he sealed his spot in the last four.
“I’m buzzing, I’m ecstatic and I’m really, really happy I’m in the semi-finals of a major,” the Belgian said.
“I’ve been doing it on the floor tournaments regularly, I’ve beaten top-10 players before so I know what I can do. I’m doing the right things at the right moments.
“I’m not thinking about it (winning it) – no chance. Tomorrow is another game and we will see from there, but I’m not dreaming about anything.”
There will be a guaranteed Belgian presence in the final after Dimitri van den Bergh defeated Joe Cullen 3-1 to set up an encounter with compatriot De Decker.
World Grand Prix: Daily schedule & results
Monday October 7 (6pm)
TV Coverage: Sky Sports
First Round (Best of three sets)
- Josh Rock 0-2 Ryan Joyce
- Brendan Dolan 0-2 Martin Schindler
- Jonny Clayton 2-0 Ritchie Edhouse
- Nathan Aspinall 2-1 Ryan Searle
- Raymond van Barneveld 1-2 Ricardo Pietreczko
- Luke Humphries 2-1 Stephen Bunting
- Rob Cross 2-1 Luke Littler
- Gian van Veen 0-2 Ross Smith
Tuesday October 8 (6pm)
TV Coverage: Sky Sports
First Round (Best of three sets)
- Dave Chisnall 2-0 Cameron Menzies
- Luke Woodhouse 1-2 Dimitri Van den Bergh
- Mike De Decker 2-1 Damon Heta
- Peter Wright 1-2 James Wade
- Gerwyn Price 2-1 Danny Noppert
- Michael Smith 1-2 Gary Anderson
- Michael van Gerwen 0-2 Daryl Gurney
- Chris Dobey 1-2 Joe Cullen
Wednesday October 9 (7pm)
TV Coverage: Sky Sports
Second Round (Best of five sets)
- Nathan Aspinall 2-3 Ryan Joyce
- Rob Cross 3-1 Martin Schindler
- Luke Humphries 3-1 Ricardo Pietreczko
- Jonny Clayton 3-1 Ross Smith
Thursday October 10 (7pm)
TV Coverage: Sky Sports
Second Round (Best of five sets)
- Gary Anderson 0-3 Mike De Decker
- Gerwyn Price 0-3 James Wade
- Daryl Gurney 2-3 Joe Cullen
- Dave Chisnall 1-3 Dimitri Van den Bergh
Friday October 11 (7pm)
TV Coverage: Sky Sports
Quarter-Finals (Best of five sets)
- Mike De Decker 3-0 James Wade
- Rob Cross 2-3 Ryan Joyce
- Luke Humphries 3-1 Jonny Clayton
- Joe Cullen 1-3 Dimitri Van den Bergh
Saturday October 12 (7pm)
TV Coverage: Sky Sports
Semi-Finals (Best of seven sets)
Sunday October 13 (7pm)
TV Coverage: Sky Sports
Final (Best of nine sets)
- Winner SF 1 v Winner SF 2
What TV channel is the World Grand Prix on?
The BoyleSports World Grand Prix will be broadcast live on Sky Sports in the UK, through the PDC's worldwide broadcast partners including DAZN and Viaplay, and on PDCTV (excluding UK, Germany, Austria & Switzerland based subscribers).
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