Yakubu celebrates after scoring
Blackburn, who started the day bottom of the table, had taken an unlikely 2-0 lead early in the second half thanks to a Yakubu double before the injury-ravaged champions drew level through two Dimitar Berbatov goals.
United had needed a point to ensure they would finish the year in top spot with leaders Manchester City not playing until Sunday but Grant Hanley's 80th-minute winner for Blackburn stopped them in their tracks.
Defeat leaves United with 45 points from 19 games, behind City on goal difference. Roberto Mancini's side can go three points clear with a victory at Sunderland.
Third-placed Tottenham Hotspur travel to Swansea City later on Saturday, with fourth-placed Chelsea hosting Aston Villa and sixth-placed Arsenal at home to Queens Park Rangers.