Johnson, who is in relaxed mood after the birth of his second son on Monday, is aiming to become the first man since Curtis Strange in 1989 to clinch back-to-back titles at the major often billed as the toughest test in golf.
This year's championship gets under way when the first pairings tee off at 6.45 am local time (1145 GMT) on Thursday.
Johnson will begin his quest at 8.35 am in a star-studded grouping with 2015 champion Jordan Spieth and 2014 winner Martin Kaymer.
Johnson, 32, missed the cut at Memorial last week and headed to Erin Hills to practice on the windswept 7,741-yard layout before returning home for the birth of his son on Monday.
"I think it sets up very well for me," Johnson said here Wednesday on the eve of his title defence.
"It's a difficult championship to win. It always plays very difficult. You've got to play good, every part of your game has to be working."
Johnson said he is still to recapture the scintillating form which propelled him to world number one earlier this year before a freak accident forced him to pull out of the Masters in April.
But with the prospect of rain on Thursday and Friday expected to make for soft conditions, favouring Johnson and the other big-hitters in the field, the American is quietly confident of his chances.
He is also buoyed by becoming a parent for the second time, stating that fatherhood has helped him ascend to the top of world golf.
"It just gives you a whole new perspective on things," he said Wednesday. "Where before kind of golf was the most important and now my family is the most important."
Another big-hitter hoping to make a mark this week is Northern Ireland's world number two Rory McIlroy, who has shaken off a niggling rib and back problem to report for duty in Wisconsin.
McIlroy plans to take a relaxed approach into Thursday's opening round as he attempts to reproduce the sort of form that saw him win four majors between 2011 and 2014.
McIlroy believes making a strong start will be the key to his chances of success.
"If you look at how I've started the majors that I've won, I've sort of led from the front," said McIlroy, who was either leading or one off the lead in the four major championships he won.
"So it is imperative for me to get off to a good start and I haven't been able to do that."
Masters champion Sergio Garcia meanwhile is aiming to follow up his maiden major triumph in Augusta with victory at Erin Hills.
Only six other players – Craig Wood, Ben Hogan, Arnold Palmer, Jack Nicklaus, Tiger Woods and Jordan Spieth – have achieved the feat. But Garcia is under no illusions about the difficulty of the challenge.
"Every tournament is tough to win and majors are even tougher," Garcia said. "And US Opens? We all know how difficult they are."
Both McIlroy and 2015 champion Spieth were critical of a decision by organisers to chop back dense fescue grass which borders fairways on the course.
United States Golf Association chief executive Mike Davis on Wednesday defended the move, saying the rain which has drenched the course this week risked making it unplayable.
Nevertheless he acknowledged organisers had sought to create the "ultimate test in golf."
"We're testing every part of the shot making," Davis said. "We're testing their course setup skills. We're testing their ability to handle their nerves, and their physical abilities."