The American only won his first professional title at last month's Wells Fargo Championship but just 43 days later he is a Major champion after a one-shot victory at The Los Angeles Country Club.
He held his nerve brilliantly in a closing level-par 70 to finish at ten under, one shot clear of McIlroy and three ahead of World Number One Scottie Scheffler.
Australian Cameron Smith was then at six under, a shot clear of Tommy Fleetwood - who became the first player to record two 63s at the U.S. Open - Min Woo Lee and Rickie Fowler.
Clark - a native of Denver - twice won the Colorado State Championship as an amateur before moving into the collegiate game at Oklahoma State.
He sadly lost his mother Lise in August 2013, and revealed this week how she instructed him to "play big" before losing her battle with breast cancer.
After transferring to the University of Oregon, he won the Pac-12 Championship in 2017 before turning professional and earned his PGA TOUR card via the Korn Ferry Tour in his debut season.
A fifth-placed finish at the Valspar Championship in March saw him enter the top 100 in the Official World Golf Ranking for the first time having been 313th last May but the World Number 32 will now have his eyes on a Ryder Cup debut in September.
"I feel like I belong on this stage and even two, three years ago when people didn't know who I was, I felt like I could still play and compete against the best players in the world," he said. "I felt like I've shown that this year.
"I've come up close, and obviously everyone sees the person that hoists the trophy, but I've been trending in the right direction for a long time now. I've made a lot of cuts. I've had a handful of top 10s and top 20s, and I feel like I've been on a great trajectory to get to this place.
"Obviously it's gone faster than I thought as far as just starting to do some stuff mentally that I've never done before, but I feel like I'm one of the best players in the world. Obviously this just shows what I believe can happen.
"But at the same time I'm a pretty humble, calm guy, and I don't try to get too high or too low on things. I'm obviously going to celebrate this, but I like to compete. I want to beat everybody but also be friends with everybody. So I try to have a good mix of that.
"I know my mom is proud of me. She's always been proud of me, regardless of how I'm doing or what I'm doing. I just wish she could be here and we could enjoy this."
Clark started the round in a tie for the lead with Rickie Fowler but it soon became clear the day was going to pan out as a two-horse race with McIlroy.
The Race to Dubai Rankings in Partnership with Rolex leader made a two-putt birdie on the par-five first to join the lead but Clark got up and down on the same hole to edge in front on his own.
A three-putt on the second had things level again but Clark put his tee-shot to five feet at the fourth and then played a smart shot from a tough lie at the sixth to similar distance to lead by two.
I know my mom is proud of me. She's always been proud of me, regardless of how I'm doing or what I'm doing. I just wish she could be here and we could enjoy this
He then left a ball in the rough as he dropped a shot at the eighth but made fantastic par saves after missing the green at the tenth and 11th to stay ahead as McIlroy recorded a series of pars.
That sequence was broken as McIlroy bogeyed the par-five 14th despite getting a fortunate drop after plugging in the face of a bunker, and Clark led by three as he two-putted the same hole after a stunning second to 20 feet.
The trophy was in Clark's hands but he missed the green at the par-three 15th and failed to get up and down and then plugged in sand off the 16th tee to drop another shot and see his advantage cut to one.
A gutsy up-and-down to save par on the 17th followed and the 29-year-old made a routine two-putt par on the last to secure the title.
Scheffler matched Clark and McIlroy with a 70, while Smith and Lee carded a pair of 67s and Fowler's challenge fell away with a 75.
Harris English and Tom Kim finished at four under, one ahead of Austin Eckroat, Dustin Johnson, Jon Rahm and Xander Schauffele.