The Englishman carded a closing 68 on his 34th birthday to get to 18 under and win by two shots, adding to his record of victories at some of the European Tour's most iconic venues.
Willett has won at Augusta National, Wentworth Golf Club and Crans-sur-Sierre to name but a few, and he can now add the Old Course at St Andrews to his list.
The two time Rolex Series champion entered the day with a three shot lead and while he was briefly caught by Richard Bland, he produced a textbook display of front running on the back nine to hold off the challenge of Tyrrell Hatton and Joakim Lagergren and become the first player to win a European Tour event on their birthday since Ernie Els at the 2004 HSBC World Match Play Championship.
This is the second time the 2016 Masters Tournament winner has tasted victory at this event, winning the team section alongside Jonathan Smart - who is back on the bag for him this week - in 2017.
Team glory this week went to Michael Hoey and Maeve Danaher at 36 under, with Danaher becoming the first woman to win the event after the pair finished at 36 under.
Ryan Fox and Australian cricketing great Shane Warne also finished at 36 under after a remarkable closing 56, but Hoey's individual score of eight under broke the tie, with Fox six shots further back.
Willett has had a testing 2021 Race to Dubai, failing to register a top ten in his first 11 events as he battled Covid-19, wisdom teeth, appendicitis and a hernia.
But he has now entered the winner's circle for the first time in just over two years and is set to move back into the top 100 in the Official World Golf Ranking.
"It's magical," said an emotional Willett. "On British soil with everyone here, it's been a great week.
"It's been a couple of years of average stuff again. I seem to do this a lot actually, go up and down.
"To win here, to be British and to be able to win on British soil, to win at the Home of Golf, this is a very special one. Especially after how the last kind of year and a half has been for everyone involved. Especially for us, we've struggled a little bit with things.
"This one, for everyone watching, this seems quite out of the blue but the practice I've been doing at home and the inner belief we have every time we get in and out of position to do something was proven again.
"Doesn't matter where it is, who it's against, it's just a question of if the game is in shape. When it is, we're all right."
Willett extended his lead to four shots with an approach to six feet at the first and while the chasing pack quickly trimmed it again, he re-established that cushion with another six footer at the third.
It's magical. On British soil with everyone here, it's been a great week
He just missed the bushes off the tee at the fourth but was in a nasty lie and when he found another with his second, he was soon just two shots clear of a group of six players.
A smart up-and-down at the par five fifth brought a third birdie of the day but the chasing pack was relentless and Willett soon once again had a large group of rivals just two back.
One of them was Bland, who hit stunning approaches into the fourth and seventh, while also taking advantage of the fifth and holing a 13 footer at the sixth.
A beautiful pitch to 13 feet from the rough at the par four ninth put him in a share of the lead but Willett drove to the fringe at the same hole and two putts edged him back ahead at the turn.
The leader came up just short of the green at the tenth but holed a 40 foot putt from off the front for a birdie and with Bland three putting ahead at the 11th, the advantage was three shots.
Swede Lagergren put approaches to 12 feet at the first and fourth for birdies and then made a move up the leaderboard with a remarkable display of putting, holing from just under 30 feet at the the fifth, seventh and eighth.
He bogeyed the 12th after finding a tricky bunker off the tee but made the most of the par five 14th and then hit the pin at the next to set up a birdie from three feet in a 66.
Two time champion Hatton made a two putt birdie at the fifth, put approaches to around six feet at the seventh and ninth and then played a stunning shot from the rough at the 12th to leave himself three feet before birdieing the last for a 67.
Bland and 2019 Open Champion Shane Lowry both signed for rounds of 68 to sit at 15 under, one clear of England's Daniel Gavins and two ahead of another Englishman in Tommy Fleetwood and South Africa's Dean Burmester.