The Australian No.1 had opted to use the tournament in s-Hertogenbosch to rebuild his shattered confidence after his French Open setback when bowing to out Jakub Mensik in the third round last month.
But despite staging a gritty fightback to draw level with Majchrzak in the climax to the Rosmalen Championships on Sunday, De Minaur eventually lost out in a final-set tie-break to succumb 6-3, 2-6, 7-6 (7-5).
The 27-year-old had looked in great shape this week when returning to his favoured grass surface after the clay of Paris, culminating in a resounding straight-sets victory over another previous winner in Frenchman Adrian Mannarino in Saturday's semi-finals.
But "Demon", who was hoping to repeat his 2024 triumph in Holland, was unable to halt World No.76 Majchrzak's remarkable run, which also saw him dispatch World No. 4 Felix Auger-Aliassime in the quarter-finals, No.8 Daniil Medvedev in the semis and now De Minaur, who remains ranked sixth.
In doing so, the 30-year-old has become just the third Polish male to lift a tour-level trophy in the Open era after Wojtek Fibak and Hubert Hurkacz and has entered the top 50 for the first time in his career.
"I don't know what to say. This is an incredible moment for me and an incredible fun and run to make this happen," he said.
"Alex is one of the toughest opponents you can face, so I knew I had to play my best to win and I think I did for the most part of the match."
Majchrzak blew a chance for a break in the third set but upped the ante in the deciding breaker to keep De Minaur shuffling around the court before seeing out victory in two hours, 25-minutes.
"I am really grateful for this moment and will really enjoy it so much. Thanks to everyone who came here," he added.
"It has been unbelievable."
De Minaur won the ATP 500 trophy in Rotterdam in February and Sunday's reversal means he missed out on emulating local hero Richard Krajicek as the only player to have won both Dutch ATP Tour titles in the same season, 1997.
But for the Sydney-born Aussie No.1, a runners-up finish in Holland continues a strong start to the grass season and he will now go to Queen's Club in London next week as top seed hoping to improve further before Wimbledon.
And typically magnanimous in defeat, he praised Mensik for his achievements.
"I'd like to congratulate Kamil and his team. Not just for today but for an unbelievable week. You deserved it today," De Minaur said in a courtside interview.
"You were the better player. It was a great battle. I just want to say too good. Congrats, mate.
"As for me, obviously would've loved to be able to get the job done today. But a great start to the grass court season.
"A good week. To my team and everyone around, we're gonna keep on building. Hopefully this is the first of many great weeks on the grass."
