Daniel Ayala nodded in the winner after opening the scoring at Deepdale, with Jonny Howson also netting for the visitors, though it was Preston who led at half-time through Callum Robinson and Jordan Hugill.
Defeat ends Preston’s unbeaten run of nine games as Alex Neil’s side were left to rue a number of missed first-half chances.
Middlesbrough snatched the lead after 13 minutes as Stewart Downing’s whipped free-kick from the left was met by Ayala, who powered a header in from 12 yards.
Preston hit back straight from the kick-off, ending their record of being the only Championship side not to score a goal in the first 15 minutes of a game this season. Tom Barkhuizen delivered a cross to the far post where Robinson headed past Darren Randolph.
Randolph was equal to Hugill after 26 minutes, getting down low to touch the striker’s flicked header from 12 yards round the post.
The Boro keeper was by far the busier and was forced to produce an excellent save to deny Robinson a second after 32 minutes, getting fingertips to a curling strike from 20 yards that was destined for the top corner.
Preston deservedly doubled their lead after 40 minutes though, Daniel Johnson picking out Hugill with a cross from the right and his header from six yards deflected off Ayala, leaving Randolph stranded.
And Alex Neil’s side came within inches of a third on the stroke of half-time when Josh Harrop’s free-kick found Tom Clarke, who headed across goal for Tom Barkhuizen but his effort from three yards hit the crossbar.
Patrick Bamford came on for Britt Assombalonga after 50 minutes and the striker almost made an immediate impact but failed to make enough contact with Grant Leadbitter’s free-kick.
Boro were level after 65 minutes thanks to a lovely finish from Howson, the midfielder showing clever feet on the edge of the area before curling a right-footed effort into the top corner.
And they came close to taking the lead four minutes later with a rapid counter-attack which culminated with Rudy Gestede firing just over from 20 yards.
Ayala doubled his tally on 73 minutes when Preston were caught out by a short corner and Adama Traore’s cross eventually found the centre-back at the far post to nod in the winner from four yards.
Newcastle have been linked with a shock move for former Sunderland goalkeeper Simon Mignolet during the summer.