Rightly billed as a blockbuster, this was a heavyweight contest played at a relentless pace with both men averaging just under a ton, but it was Anderson who consistently won the moments that mattered.
He landed 11 maximums to Van Gerwen's haul and, despite neither player excelling on the doubles, the Scot was fractionally sharper when pressure peaked, converting 13 of 34 attempts to Van Gerwen's 9 from 29.
Anderson set the tone immediately, claiming a high-quality opening set that featured heavy scoring, four maximums from the Scot and a composed 14-dart decider.
Van Gerwen responded with flashes of vintage brilliance, including a blistering 10-darter in set three as he briefly dragged the match back under control, but it proved a false dawn.
Anderson repeatedly punished missed doubles from the Dutchman, breaking throw with ruthless efficiency and refusing to yield ground once in front.
Even when chances slipped, including a missed match dart at the bull for 121, Anderson remained unflustered, trusting his scoring power to bring him back to the board.
By the time the fourth set slipped away in scrappy fashion, Van Gerwen was forcing finishes and burning darts at the outer ring, while Anderson stayed patient. A 15-dart hold in the final decider, finished on double eight, sealed a result that felt both emphatic and symbolic.
It marks a landmark win for Anderson and a rare early exit for Van Gerwen, whose long-standing grip on the latter stages of this tournament finally loosened.
The Flying Scotsman - who averaged 99.1 - now advances to face Justin Hood in the quarter-finals, carrying momentum, confidence and the quiet authority of a champion who still knows exactly how to win on this stage.
'One of those games'
"I knew Michael misses a few doubles now and again, but not that many," Anderson told Sky Sports after his win.
"Happy to get through. I've never felt right since I got on the stage tonight, and I don't think he felt right.
"I was trying to feed off him. It was one of those games.
"I was on doubles every leg before him, but I was 2-1 down, and I won it 3-2. I know if he gets in front of you, he's a hard man to catch.
"Justin Hood is a cracking darts player. He's done fantastic. Same as Charlie tonight and Kevin Doets. It's been a cracking tournament."
Humphries powers through
Luke Humphries produced a blistering response to early danger as he swept Kevin Doets aside 4-1, storming into the quarter-finals with one of his most complete performances of the tournament.
After a nervy opening set slipped away, Humphries raised the temperature sharply. Doets had made a fearless start, landing a 177, threatening a nine-darter and breaking twice to claim the opener, but the world number two steadied himself immediately. From the second set onwards, the contest tilted decisively.
Humphries broke early in set two, powered by heavy scoring and back-to-back maximums, and never relinquished control. His timing was ruthless, punishing missed doubles and capitalising whenever Doets' scoring dipped.
By the fourth set, the pressure was suffocating. Even Doets' landing the 1000th 180 of the tournament merely delayed the inevitable, as Humphries raced through a seven-minute whitewash to move within touching distance of victory.
The fifth set was emphatic. Humphries reached a finish after nine darts, tidied up clinically and closed the match with calm authority, pinning double eight to seal a 4-1 win that felt decisive long before the final dart was thrown.
Humphries averaged 103.07, hit eight 180s and converted 48 per cent of his doubles, numbers that reflected not just dominance but control. Doets played his part and showed flashes of real quality, yet once Humphries found his rhythm, the gap was unmistakable.
The win sets up a mouth-watering quarter-final against Gian van Veen.
Van Veen halts Manby
The win for Humphries sets up a mouth-watering quarter-final against Gian van Veen, with the young Dutchman ending Charlie Manby's dream debut run with a 4-1 victory earlier in the evening.
Van Veen burst out of the blocks in the opening set, racing through legs with heavy scoring and twice threatening nine-darters. Manby competed well early and forced a decider, but Van Veen held his nerve, finishing tops after nine darts to edge the set 3-2.
The 20-year-old Englishman responded impressively in the second, punishing rare slips from the Dutchman with a 107 checkout and taking control of the set with calm authority on the doubles to level the match. It proved a brief interruption rather than a momentum shift.
From there, Van Veen took charge. The third set turned on a moment of pure class, a bold 132 checkout on the bull, while the fourth was brutally one-sided as he stormed to a 3-0 whitewash, pinching legs with clinical bull finishes and relentless pressure.
Van Veen tightened his grip with another maximum in the fifth set, steadied after a scrappy spell on the doubles and extinguished any lingering hope in the decider, sealing the match on his favoured double 16. His ninth 180 of the contest underlined the gap in scoring power.
Van Veen finished with a near-ton average, comfortably outperforming Manby on maximums and delivering key ton-plus checkouts at decisive moments.
Tuesday evening session results:
Charlie Manby 1-4 Gian van Veen
Michael van Gerwen 1-4 Gary Anderson
Luke Humphries 4-1 Kevin Doets