Englishman Donald had been a stroke in front with five holes remaining when play was suspended in fading light on Thursday but slipped back with three-putt bogeys at the par-four 16th and par-four last to card a two-under-par 68.
Tournament favourite Tiger Woods, a four-times winner on the 2013 PGA Tour who is seeking his first major title in five years, finished with a 73 after covering his final eight holes in one over on a chilly, damp morning at Merion Golf Club.
Mickelson had set the pace in the year's second major with a four-birdie 67 the previous day, starting his round only a few hours after returning to Merion on an overnight flight from his native California.
Only three other players in the field of 156 ended the opening round under par, Australian Mathew Goggin carding a 68 while Belgian Nicolas Colsaerts and Scotland's Russell Knox returned 69s.
Donald was tested to the full over the difficult five-hole closing stretch after he resumed his opening round on Merion's fabled East Course where the wind had switched direction from Thursday.
"The tough holes are extremely tough," Donald told reporters after finishing up par, par, bogey, par, bogey.
"It does give you a little bit of balance with some of those shorter holes, but you really need to play those tough ones well."
Asked what had led to his three-putts after he had reached both the 16th and 18th greens in regulation, Donald replied: "Misreads.
"I misread both the longer putt and the short putt (on 16). Both of them I thought were slightly right-to-left and they turned three or four feet right-to-left.
"(On 18) I thought I hit that soft enough for it to break, but it didn't," he added, referring to a four-footer for par which slid past the left edge of the cup.
Donald then set off to grab a light lunch as he had only about 90 minutes before starting the second round.
Several other players lost ground in the upper reaches of the leaderboard as Merion showed its teeth for a second successive day with penal rough and challenging greens.
Masters champion Adam Scott, three under overnight, dropped five shots in his last seven holes to post a 72. Reigning U.S. Open champion Webb Simpson bogeyed three of his last eight holes for a 71.
Northern Irish world number two Rory McIlroy, playing in the same group as Scott and Woods, covered his final seven in three over par for a 73.
"I struggled coming in there this morning," said McIlroy, winner of the 2011 U.S. Open at Congressional.
"Conditions were a little trickier than they were last night. The wind got up and a couple of the holes were playing quite long."
Woods again struggled on Merion's sloping greens as he mixed three birdies and five bogeys in his opening round.
"I left myself quite a few putts in there where they were easily makeable and I didn't make any," the American world number one said.
"I had two three-putts and a boatload of putts so the round could have easily been under par."
Woods had winced on several occasions on Thursday and shook his left arm as he played out of Merion's thick rough but was reluctant to talk much about it on Friday.
"It is what it is and you move on," Woods said.
England's former world number one Lee Westwood briefly shared the lead at three under with Mickelson on Thursday but tumbled backwards with a double-bogey at the 12th after hitting one of Merion's distinctive wicker baskets atop the pin with his approach.
Though he covered his last five holes on Friday morning in one over, he was happy to be in contention for a first major title by starting with a 70.
"It's a good start," Westwood said. "I played nicely yesterday and then came out this morning and the conditions were a little bit different.
"It was quite cold and damp and a little wet, so I think 70 is a good score and I'm in decent position."
Collated first round scores of the 113th US Open golf championship at 6 996-yard, par-70 Merion Golf Club:
67 - Phil Mickelson (USA)
68 - Luke Donald (ENG), Mathew Goggin (AUS)
69 - Nicolas Colsaerts (BEL), Russell Knox (SCO)
70 - Charl Schwartzel (RSA), Tim Clark (RSA), Jerry Kelly (USA), Rickie Fowler (USA), Jason Day (AUS), Peter Hedblom (SWE), Lee Westwood (ENG), John Senden (AUS), KJ Choi (KOR), Branden Grace (RSA)
71 - Bubba Watson (USA), Dustin Johnson (USA), Steve Stricker (USA), Justin Rose (ENG), George Coetzee (RSA), Charley Hoffman (USA), John Huh (USA), Ian Poulter (ENG), Kevin Phelan (IRL), Estanislao Goya (ARG), Michael Thompson (USA), Gonazlo Fernandez-Castano (ESP), Webb Simpson (USA), Ernie Els (RSA), Kyle Stanley (USA), Hideki Matsuyama (JPN)
72 - Hunter Mahan (USA), Stewart Cink (USA), Shawn Stefani (USA), Nicholas Thomson (USA), Mike Weir (CAN), Pan Cheng-Tsung (TPE), Adam Scott (AUS), Carl Pettersson (SWE), Kevin Chappell (USA), Kevin Streelman (USA), Matt Bettencourt (USA), Billy Horschel (USA),Bio KIm (KOR)
73 - Nick Watney (USA), Paul Casey (ENG), Marcel Siem (GER), Sergio Garcia (ESP), Padraig Harrington (IRL), Michael Kim (USA), Chris Doak (SCO), Jaco Van Zyl (RSA), Kevin Sutherland (USA), Ryan Nelson (USA), Tiger Woods (USA), Rory McIlroy (NIR), Jamie Donaldson (WAL), Luke Guthrie (USA), Edward Loar (USA), Bo Van Pelt (USA), Max Homa (USA), Steven Alker (NZL), Alistair Presnell (AUS), Jesse Smith (USA)
74 - Peter Hanson (SWE), Lucas Glover (USA), Matt Kuchar (USA), Brandt Snedeker (USA), David Lingmerth (SWE), Martin Laird (SCO), Jason Dufner (USA), Henrik Stenson (SWE), Simon Khan (ENG), Jay Don Blake (USA), Brandt Jobe (USA), Randall Hutchison (USA), Geoff Ogilvie (AUS), Angel Cabrera (ARG), Zach Johnson (USA), Michael Weaver (USA), Josh Teater (USA), Morten Orum Madsen (DEN), Gavin Hall (USA)
75 - Cliff Kresge (USA), Aaron Baddeley (AUS), Louis Oosthuizen (RSA), Boo Weekley (USA), Matteo Manassero (ITA), Ryan Palmer (USA), Douglas Labelle (USA), Matt Weibring (USA), John Hahn (USA), Mackenzie Hughes CAN), David Toms (USA), Jose Maria Olazabal (ESP), Brian Stuard (USA), Scott Langley (USA), Chris Williams (USA), Joe Ogilvie (USA), Hwang Jung-Gon (KOR), Brandon Brown (USA)
76 - Ryan Yip (CAN), John Parry (ENG), Ted Potter (USA), Michael Campbell (NZL), Wil Collins (USA), Harold Varner (USA), Justin Hicks (USA), Paul Lawrie (SCO), Brendan Steele (USA), Martin Kaymer (GER), Grame McDowell (NIR), Morgan Hoffmann (USA), Steven Fox (USA), Jim Herman (USA)
77 - Bill Haas (USA), Keegan Bradley (USA), Rory Sabbatini (RSA), David Howell (ENG), Jim Furyk (USA), Eddie Pepperell (USA), D.A. Points (USA), Bae Sang-Moon (KOR), Russell Henley (USA), Jordan Spieth (USA)
78 - Rikard Karlsberg (SWE), Yui Ueda (JPN), David Hearn (CAN), Geoffrey Sisk (USA), Marc Leishman (AUS), Francesco Molinari (ITA), Scott Piercy (USA), Yoshinobu Tsukada (JPN), John Nieport (USA), Matt Harmon (USA)
79 - Ryan Moore (USA), Marcus Fraser (AUS), Casey Wittenberg (USA), Thongchai Jaidee (THA), Thorbjorn Olesen (DEN)
80 - Roger Tambellini (USA), Robert Garrigus (USA), Darren Clarke (NIR)
81 - Andre Svoboda (USA), Cory McElyea (USA), Adam Hadwin (CAN), Ryan Sullivan (USA), Brandon Crick (USA)
82 - Zack Fischer (USA)
83 - Grayson Murray (USA)