Fowler, playing in his first U.S. Open since 2020, will set off with Clark at 3:40 p.m. PT (2240 GMT) in the final pairing at Los Angeles Country Club where 65 players from the 156-man starting field made the cut.
Fowler has been stuck on five PGA Tour victories since 2019 and despite his on-course struggles over the years, has remained one of the most popular players on the US based circuit.
Fowler has already made a mark this week as his two-day 130 total tied the lowest 36-hole U.S. Open scoring record set by Martin Kaymer in 2014. He also set a tournament record with 18 birdies through 36 holes.
"Having a lead right now doesn't really mean much. A little different once you get to after 54 holes because that's when things really heat up," Fowler said on Friday.
Fowler, who also held a share of the first-round lead with Schauffele, will have his work cut out with a leaderboard that features plenty of top-tier talent.
Clark, who beat a stacked field at Quail Hollow for his first PGA Tour victory last month, made the cut for the first time in three US Open starts and will look to cash in on his best 36-hole position in a major championship.
World number three McIlroy, who has gone nearly nine years since winning his fourth major title, will set off in the penultimate group alongside Schauffele two strokes off the lead.
Schauffele, who is ranked sixth in the world, is seeking his first major triumph and boasts top-15 finishes in all six U.S. Open starts, the longest streak at the event since Lanny Wadkins had six straight from 1981-86.
World number one Scottie Scheffler, trailing Fowler by five, and British Open champion Cameron Smith, six back, were scheduled to go off at 2:56 PT.
Masters champion Jon Rahm, who extended the longest active streak of made cuts in majors to 16, was 12 shots off the lead and went out early with Canada's Adam Hadwin.
