Menzies' stunning win over world number two Humphries made it successive nights for Scottish triumphs after Gary Anderson's stellar performance on Sunday.
Appearing in only his second World Matchplay, Menzies produced a superb finishing display to register his first victory on the Winter Gardens stage.
After seven straight breaks of throw to open the contest, including a 129 checkout from Menzies and a 167 finish from Humphries, the Scot moved 8-3 ahead.
Humphries responded by taking the next four legs, but Menzies restored his composure with a 98 checkout before sealing the biggest win of his career with a sensational 170 finish.
"No matter what I do in my life, I will take this to my grave," Menzies said.
"No one gave me hope. I didn't give myself hope, (but) I've finally won a game at the Winter Gardens!
"To beat someone as amazing as Humphries on this stage... that's my biggest win in the PDC."
Menzies will now face Ross Smith in the second round after the former European champion overcame a spirited fightback from debutant Kevin Doets.
Smith raced into a 5-0 lead, helped by a 10-dart leg and a 160 checkout, before Doets cut the deficit to 6-4.
The Englishman moved to within one leg by winning three in a row, and although Doets produced a 161 finish to extend the match, Smith wrapped up victory with a 120 checkout.
Gerwyn Price also came from behind to beat Martin Schindler 11-9 and record his sixth first-round win on the bounce in Blackpool.
The Welshman trailed 4-0 and 6-2 before recovering to lead 9-8, only for Schindler to force a tie-break with a 121 checkout.
Price immediately broke throw before taking out 100 to complete the turnaround.
"Without the crowd, I would have lost today," Price said.
"It was probably the worst I've played all season. It was a tough one for me. I'm low on confidence at the minute because I haven't played a lot.
"That's probably one of those games I should have lost, but I've won. I'm still in the tournament."
Price will face Rob Cross in the second round after the former world champion completed the opening round with a comfortable 10-3 victory over Danny Noppert.
Round two begins on Tuesday, with defending champion Luke Littler taking on Nathan Aspinall, Michael van Gerwen facing Dirk van Duijvenbode, Jonny Clayton meeting Gary Anderson and Stephen Bunting playing Josh Rock.
Monday's results
Ross Smith 10-6 Kevin Doets
Gerwyn Price 11-9 Martin Schindler
Cameron Menzies 10-7 Luke Humphries
Rob Cross 10-3 Danny Noppert