Knowing a win would move them out of the bottom three for the first time this year, Oxford started brilliantly as Helik chested down Cameron Brannagan’s long free-kick from halfway and shinned a finish past goalkeeper David Cornell.
Brown headed over when unmarked, and a moment later, Osmajic found a yard of space to meet Ben Whiteman’s fine cross and head in from close range.
More shaky defending drew boos from the home fans as Jamie Donley was given space to cushion a shot just past the post before Stan Mills was allowed to run from deep in his own half into the Preston penalty area but blazed over.
Lankshear did well to block Whiteman’s goalbound volley, but the Tottenham loanee striker was found wanting at the other end when played in on goal as a poor first touch allowed Cornell to smother.
The U’s had mustered just nine second-half goals in the Championship this season and may have feared their chance of a fourth away win of the campaign had gone.
But Lankshear made amends for his earlier miss as he stuck out a toe to divert Mills’ low shot just inside the right-hand post with Preston’s back line again caught ball watching.
And the hosts’ soft centre was exposed again as Myles Peart-Harris’ long throw was flicked on for Brown who outmuscled Lewis Gibson to steer in a close-range finish and equal Oxford’s biggest win of the season.
The Lilywhites pressed in a desperate bid to salvage something, but Jordan Thompson’s snapshot, beat clear by U’s keeper Jamie Cumming, was the best they could muster as they limped to a fourth home defeat in their past six matches.