A goal apiece from Ricardo Fuller and David Healy inside three sensational second-half minutes sent Preston leapfrogging over the Hammers into fifth spot.
And having lost four of their last six home matches West Ham again fell behind in the promotion race.
"We've made Upton Park a hostile stage by the manner of our performances," said dejected Alan Pardew.
"We look like promotion contenders away, but here at home we are very nervous. We've got to be brave because this is a tough stage.
"I need to look at bringing in some characters who can handle the pressure of playing in a big stadium, because we've got no automatic right to go straight back up." Just one point and one place had separated these sides but there was nothing to chose between them during the opening exchanges.
Michael Carrick's 20-yarder was parried by visiting keeper Jonathan Gould, before Don Hutchison wastefully scuffed wide for the Hammers.
At the other end, Brian O'Neil sent an angled header inches wide for North End who also saw the lively Fuller twice denied.
In the 19th minute, however, the deadlock was broken when Matthew Etherington galloped away from well inside his own half before sending a low, cross into the six-yard box where David Connolly side-footed home his tenth goal of the season.
The alert David James prevented an instant Preston response when he plucked Healy's quickly taken 25-yard free-kick from under the angle.
With both sides eager to climb into those play-off berths, passions were running high as Healy, Michael Keane, Claude Davis and Don Hutchison all saw yellow before the hour mark.
But when Marlon Harewood became the fifth player to be booked midway through the half for not retreating ten yards it proved costly.
For Graham Alexander's twice-taken free-kick was nodded back across the face of goal by Chris Lucketti and Fuller equalised with the simplest of headers.
Moments later only James' knees denied the Jamaican striker a quick-fire second, but Preston were now on the up and on 67 minutes Healy collected Alexander's short corner and fired them ahead with an angled near post shot.
Having seen their lead evaporate United were lucky not to fall even further behind as Richard Cresswell splintered the bar and then the post with two fierce shots.
Throwing caution to the wind Pardew pitched on both Brian Deane and Neil Mellor, but neither his four forwards nor a late upfield dash from James could prevent Preston from following up their one and only victory at Upton Park, which came as long ago as October 1949, with a second win.
"It was a good recovery but we shouldn't have needed a comeback because we shouldn't have been behind in the first place," said Craig Brown.
"We had a realisation we could come back. We've only lost one of our last 14 games and we've just got to keep on playing as we are because we've got a realistic chance of making the play-offs."