Emil Hallfredsson whipped in a corner but it was punched away by Preston goalkeeper Andy Lonergan in the fourth minute.
Barnsley opened the scoring in the eighth minute courtesy of a 25-yard deflected low right-foot strike by Anderson De Silva, who dispossessed Richard Chaplow and got through two tackles before finding the bottom left corner with Lonergan having no chance.
De Silva had another shot comfortably saved after 19 minutes and Ryan Shotton had a cross saved three minutes later.
Preston equalised in the 27th minute when centre-back Darren Moore misjudged a backpass and striker Danny Welbeck, in front of watching Manchester United boss Sir Alex Ferguson, nipped in and slotted the ball in from close range for his second goal in two games.
Chaplow sustained a hip injury and was replaced by Darren Carter after 29 minutes.
A left-foot left-wing Ross Wallace corner found Billy Jones and he hit the post with a right-foot shot from 15 yards after 33 minutes.
A left-foot Hallfredsson corner found Stephen Foster and his header led to Michael Hart slicing into the roof of his own net after 41 minutes as the Tykes regained the lead.
Neil Mellor hit the bar with a left-foot volley from 20 yards after 45 minutes and soon after half-time Carter crossed to Mellor and his shot was saved.
Andy Gray's close-range header hit the post from Carl Dickinson's cross after 53 minutes.
Debutant Keith Treacy replaced Mellor in the 56th minute and Carter fouled De Silva and was booked two minutes later.
De Silva had a shot saved in the 59th minute and Hart's cross was blocked two minutes later.
Andy Gray made it 3-1 from close range after 69 minutes into the top right corner of the net after Nathan Doyle's assist.
Billy Jones' cross was saved after seventy minutes and Eddie Nolan's cross was saved after 79 minutes.
De Silva was booked for a foul on Nolan in the 87th minute by referee Nigel Miller from County Durham.
Recent loan signing Jay Rodriguez replaced De Silva in added time and made it 4-1 from close range following a Gray cross.