Yakubu scored twice as Middlesbrough ended Preston's 25-match unbeaten run to reach the last eight of the FA Cup.
Yakubu (right) scored a brilliant opening goal
The striker put Boro ahead with a ferocious left-foot strike early in the second half and then headed his second after Claude Davis failed to clear.
Preston dominated much of the match, with David Nugent and Patrick Agyemang both going close several times.
Boro keeper Mark Schwarzer saved a Youl Mawene header, while Paul McKenna went close with a free-kick.
The result was tough on the home team, who were looking to reach the quarter-finals of the FA Cup for the first time since 1966.
Billy Davies' side contributed much to the match but Boro defended well for large periods and showed that in Yakubu they have a striker of real quality.
The one low point for Boro was an injury to Fabio Rochemback, who was carried off on a stretcher before half-time after injuring his left foot.
Preston had by far the better of an opening half that was high on endeavour but low on incident.
Rochemback deflected a cross into the hands of Schwarzer and Nugent drilled a long-range strike narrowly wide as North End made the early running.
Nugent looked to pick up the ball in wide areas and run at goal whenever possible - and the 20-year-old forced Schwarzer into action with another long-range strike after 20 minutes.
Mawene lost his marker at a free-kick but his header was well wide, while Preston had a penalty appeal turned down for a handball by Emanuel Pogatetz.
The home team's passing and movement was impressive but they were almost caught out when Mawene found himself isolated with Yakubu on the ball.
Rochemback was carried off before the break
Yakubu went down under Mawene's challenge but referee Phil Dowd waved play on.
Rochemback turned his ankle after his foot caught in the heavy turf as he tried to avoid a late challenge from Callum Davidson at the end of a frustrating 45 minutes for the visitors.
Boro boss Steve McClaren tried to increase his team's attacking threat at the break, introducing Jimmy Floyd Hasselbaink for Tony McMahon.
And Hasselbaink had a hand in Boro's opener, with Yakubu collecting his flick before taking the ball past the North End defence with a header and smashing the ball past Carlo Nash from 20 yards.
Agyemang almost equalised in equally spectacular fashion but his 25-strike flew wide of Schwarzer's goal.
The Preston striker hit the target with another effort but this time his shot lacked power, while Nugent drilled a long-range strike inches over the Boro crossbar.
North End continued to press and Schwarzer made a good save to deny Mawene with a header, while McKenna was inches wide of the goal with a free-kick.
But Preston defender Davis made a bizarre decision not to clear a free-kick and was punished when Yakubu put Boro two ahead with a diving header at the far post.
Preston boss Billy Davies on his team's unbeaten run:
"It has come to an end and we knew that at some stage that was going to happen.
"I am disappointed but very proud of the performance. We will learn one or two things from the game and move on.
"It was important to get a goal in the first half because against that opposition it only takes one mistake."
Middlesbrough boss Steve McClaren:
"It was a tough game. All credit to Preston, who took us to down to the wire.
"We did not play well and we really had to grind out a result. We defended well and have players who can score goals.
"We are becoming hard to beat and if we continue like that we will do well. We have got key personnel back."
Preston: Nash, Mears, Mawene, Davis, Hill, Sedgwick (Lewis Neal 67), McKenna, O'Neil (Dichio 68), Davidson, Agyemang (Lucketti 82), Nugent.
Subs Not Used: Hibbert, Ward.
Booked: Mawene, Davidson.
Middlesbrough: Schwarzer, McMahon (Hasselbaink 45), Riggott, Pogatetz, Queudrue, Parnaby, Mendieta, Boateng, Rochemback (Cattermole 45), Downing, Yakubu (Southgate 81).
Subs Not Used: Jones, Taylor.
Booked: McMahon, Hasselbaink.
Goals: Yakubu 52, 77.
Ref: P Dowd (Staffordshire).