In front of a crowd of 87,122 at the MCG, the Blues took a 1-0 series lead after a hard-fought and fluctuating match that saw a number of fresh faces step up to the Origin challenge.
The Blues held onto a 8-6 lead at the break and fell behind early in the second half, but powered home to score the final three tries.
Rookies Latrell Mitchell, Tom Trbojevic and Josh Addo-Carr all crossed, as did fullback James Tedesco who was the Blues' best.
It was billed as the start of a new era in State of Origin.
And while Queensland showed signs of life after the Big Three, the Maroons' days of dominance may be numbered after NSW claimed the series opener.
The Baby Blues - boasting 11 rookies - came of age against a Maroons side without retired greats, ex-skipper Cameron Smith, Johnathan Thurston and Cooper Cronk.
NSW was the greenest Origin side in 37 years after unveiling an unprecedented list of debutants under rookie coach Brad Fittler.
But what they lacked in experience they made up with their much-vaunted backline firepower led by a man-of-the-match performance by full-back James Tedesco who scored the opening try.
It capped a horror week for the rebuilding Maroons.
The signs were ominous for Queensland after a chaotic lead-up, losing veteran full-back Billy Slater (hamstring) and sweating until the last minute for the availability of winger Dane Gagai (finger).
The Maroons were already without 151 Origin games' worth of experience.
And their luck didn't change on Wednesday as the most inexperienced Maroons side in more than a decade could not stop NSW registering Origin win number 50 - albeit six years after Queensland had notched the same landmark.
The Blues - boasting just 39 games of Origin experience - will hope they have started a new Origin era after the Maroons claimed 11 of the last 12 series.
New skipper Greg Inglis did his best to step up in the Big Three's absence, laying on some inspirational tackles.
And at first it seemed to work.
Inglis' 27th minute hit on Tom Trbojevic gave the Maroons a lift before winger Valentine Holmes scored an 85m intercept try a minute later to cut the deficit to 8-6 at half-time.
And Queensland threatened to pull off another unlikely win when they led 12-8 after Gagai scored in the 43rd minute.
But there was no denying the Blues who finally lived up to bookies' favouritism as they ran in three second half tries through Latrell Mitchell (48th), Tom Trbojevic (50th) and Josh Addo-Carr (70th).
It could have been worse - centre Mitchell and wing sensation Addo-Carr were denied tries.
Queensland must regroup before game two on June 24 in Sydney.