A makeshift Barcelona team fell to a 2-0 loss at Deportivo La Coruna on Saturday meaning Real Madrid now have the chance to win the title on Sunday if results go their way.
With one eye on Tuesday's Champions League semi-final against Manchester United coach Frank Rijkaard rested several key players – such as Lionel Messi, Andres Iniesta and Xavi – and the second string were second best against a motivated Depor team.
Barca stay 11 points behind Real in third and the reigning champions can wrap up a 31st championship on Sunday if they beat Athletic Bilbao and Villarreal fail to win at Real Betis on the same day.
Wrestling second spot from Villarreal, a point ahead with a game in hand, is one challenge for Barca but top priority is now the Champions League.
Barca drew 0-0 in the first leg at Camp Nou and go to Old Trafford looking for a vital away goal to help them reach the Moscow final.
Messi, Samuel Eto'o, Xavi, Iniesta, Gaby Milito, Deco and Victor Valdes were all notable absentees in the Barca line-up with Rijkaard clearly keeping them fresh for Manchester United.
The second string team saw Spaniard Jose Pinto, virtually unknown to Barca supporters, start in goal but there was still some quality on show with three World Cup winners in Thierry Henry, Gianluca Zambrotta and Lilian Thuram.
Eidur Gudjohnsen, a fringe player hoping to impress, should have scored on 12 minutes but lifted an effort over the crossbar.
Barca dominated possession but Depor went close to breaking the deadlock on the half hour mark when Xisco hit the crossbar.
Bojan Krkic then spurned a great chance delaying his shot too long.
The misses proved costly as Juan Rodriguez side-footed home at the beginning of the second half with some woeful Barca marking.
Pablo Amo added a second as Depor, who have been fighting relegation for most of the season, moved a point from the final UEFA Cup spot.
Sevilla travel to Real Murcia in Saturday's late match looking to edge away from Depor and move level on points with fourth-placed Atletico Madrid.
Atletico have occupied the final Champions League slot for most of the season but have a difficult local derby at Getafe to contend with on Sunday.
Racing Santander are just a point behind Atletico but also have a difficult trip to Real Mallorca on the same day.
Valencia were in the Champions League quarter-finals last season but the Kings Cup winners are trying to stay in the league when they face Osasuna on Sunday.
Valencia are just two points above the drop zone and hope the dismissal of under-performing manager Ronald Koeman can keep them in the top-flight.
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