Red Devils humbled once again at home in Europe as the Basque side produce a dominant performance at Old Trafford to make themselves favourites to progress
The home side took the lead against the run of play through Wayne Rooney before Fernando Llorente equalised with a powerful header on the brink of half-time.
Oscar De Marcos turned home a wonderfully crafted second for the visitors and Iker Muniain hit a late third before Rooney turned home a penalty in stoppage-time to round off a thrilling affair.
United made five changes to their side, Phil Jones moved into midfield as Chris Smalling was reintroduced to the defence and Javier Hernandez partnered Rooney in attack.
Athletic made one change to the side that beat Real Sociedad in Sunday's Basque derby, highly-rated midfielder Javi Martinez moved into defence to cover the suspended Fernando Amorebieta with Ander Iturraspe coming into the middle.
|MUNIAIN MESMERISES IN MANCHESTER
The Spanish side made an assured start to the match and went close to taking a deserved lead in the fourth minute as Llorente fired just wide after displaying nimble feet on the edge of the area
United were struggling to cope with Bilbao's fluid formation and the Spaniards had a good shout for a penalty turned down as Llorente was dragged to the turf by Smalling.
Just as an Athletic goal looked imminent Sir Alex Ferguson's side, as they so often do, struck the first blow. Ryan Giggs bundled his way through midfield before exchanging passes with Hernandez, the Mexican turned sharply in the box only to see his effort saved by Gorka Iraizoz but Rooney was on hand to follow in and smash home.
The goal could have sucked the life from Marcelo Bielsa's side but they persevered with Llorente unlucky to see his header fly over the bar before Markel Susaeta could only chip wide when through on De Gea's goal.
Andoni Iraola tried to sneak an effort in at the near post before Athletic grabbed a richly-deserved equaliser just before the break. Susaeta was given too much space by Evra and picked out the on-rushing Llorente who planted a firm header into the net and sent the 6,000 travelling fans into ear-shattering delirium.
The Lions came out for the second half as though the break hadn't happened, Muniain's 20-yard drive brought a magnificent sprawling save out of compatriot De Gea before the 21-year-old made another stunning stop to deny Llorente's curled effort.
United were forced to reshuffle their pack as Smalling's head wound, sustained in England's defeat to the Netherlands, re-opened and Michael Carrick was brought on in his place with Jones moving back into the defence.
Hernandez was looking the most potent of the home side's strikers but the Mexican could not find space in the box and saw two efforts blocked.
A change was needed and Ferguson responded, sending Anderson on in place of Park Ji-Sung, moving Giggs to the left flank.
United were still looking sluggish and once again had De Gea to thank for keeping the score down as he blocked Muniain's effort after a great twisting run from the teenage attacker.
Following that scare, the home side went straight up the other end to give Hernandez the opportunity to equalise but the forward's touch from Giggs' ball got away from him and Iraizoz was able to smother the ball.
The Basque outfit were undoubtedly the better side and scored their second goal with 20 minutes remaining. Muniain and Susaeta combined brilliantly through the middle to bypass Anderson before Ander Herrera chipped an excellent ball to De Marcos who swept the ball past De Gea first time to give Athletic the lead.
Nani was sent on in place of Giggs as United chased an unlikely and undeserved equaliser and Rooney hit a rasping effort into the gloves of Iraizoz before Llorente was substituted to thunderous applause from the Basque supporters.
Athletic further extended their lead late on in controversial fashion. A free-kick, awarded at the edge of the Bilbao box after Evra played the ball with only one boot on, was lumped forward by the visitors and, after De Gea saved De Marcos' initial effort from the flick-on, Muniain raced in to tap home a third.
Rooney smashed home a late penalty to narrow the deficit after a handball but United will have much work to do if they are to salvage the tie in a week's time.
Commentaries, Stats, Player Ratings and much more,
Visit Goal.com Live Scores!