Manchester United lost more ground on Chelsea at the top of the table after a woeful display at the Riverside.
Edwin van der Sar gifted Middlesbrough the lead when he let Gaizka Mendieta's shot slip through his fingers.
A mistake by Rio Ferdinand let in Jimmy Floyd Hasselbaink for the second, and Yakubu Ayegbeni made it 3-0 from the spot after Stuart Parnaby was fouled.
Yakubu set up Mendieta to make it 4-0, and even Cristiano Ronaldo's header did not take the shine off Boro's victory.
Sir Alex Ferguson's side play Chelsea at Old Trafford on 6 November but will go into that game already 13 points adrift of the leaders - albeit with a game in hand - and with their title hopes hanging by a thread.
The writing was on the wall for them here after just two minutes when Van der Sar's mistake allowed Boro their opener.
Mendieta's whipped shot had plenty of power behind it, but it should still have been easily gathered by the Dutch international.
And the Spanish international almost added a second soon after. He picked up the loose ball after Ferdinand had cut out George Boateng's pass and skipped clear before shooting just over the bar.
United did have chances at the other end - with John O'Shea going closest - but their lethargy at the back meant it was no surprise when Boro's second goal arrived on 25 minutes.
Ferdinand hesitated as Mendieta's long ball bounced in the area, and Hasselbaink muscled him off the ball before blasting home a shot that Van der Sar could not keep out of the net.
Ferguson's response was to reshuffle his backline - Kieran Richarson replacing Phil Bardsley and slotting in on the left, with O'Shea moving over to the right.
It seemed to have done the trick, with Boro briefly forced on to the back foot, and Ruud van Nistelrooy almost pulled a goal back with a low shot on the turn that Mark Schwarzer turned around the post.
But any thoughts of a United comeback were ended just before half-time.
Parnaby ran on to Hasselbaink's ball into the box but was hauled back by Richardson and after consulting his assistant, referee Alan Wiley pointed to the spot.
A sustained protest by Ferdinand and Van der Sar failed to change the official's mind, and after some delay, Yakubu stepped up to coolly roll the ball home.
Boro were happy to sit on their lead after the break and although United had the lion's share of possession, they found it impossible to break down their opponents.
There was no shortage of effort by Rooney and Van Nistelrooy up front but with Chris Riggott in outstanding form at the centre of defence, Boro always looked comfortable.
Steve McClaren's side were also dangerous on the break, with Hasselbaink twice failing to make the most of dangerous opportunities.
Even when Ronaldo came off the bench with half an hour to go, United struggled to create a clear-cut opening.
But there was still more to come from Boro.
Yakubu made good progress down the left flank and pulled the ball back for Mendieta, who found the net with a first-time shot for his second and his side's fourth.
Ronaldo did head home a consolation deep in injury time for United - their 1,000th Premiership goal - but by then the home fans had long been celebrating a famous victory.
Middlesbrough manager Steve McClaren:
"I told the players afterwards that they should enjoy themselves because moments like this do not come along too often.
"We deserved it, the players were fantastic. We played some good football and scored some very good goals.
"We had to impose our system on theirs. We did that and it was a platform for our win. We have been waiting for this kind of performance and result."
Manchester United boss Sir Alex Ferguson:
"It was a shocking performance. We conceded some terrible goals and we cannot afford do that with what we are trying to achieve.
"We conceded in the second minute to a free shot from 25 yards and we never recovered from that."
"A lot of people look at us as a team who can stop Chelsea - but not on this showing."
Middlesbrough: Schwarzer, Bates, Riggott, Queudrue, Parnaby, Boateng, Mendieta (Morrison 87), Rochemback (Doriva 64), Pogatetz, Hasselbaink (Nemeth 79), Yakubu.
Subs Not Used: Jones, Viduka.
Goals: Mendieta 2, Hasselbaink 25, Yakubu 45 pen, Mendieta 78.
Man Utd: Van der Sar, Bardsley (Richardson 31), Ferdinand (Brown 87), O'Shea, Silvestre, Fletcher, Smith, Scholes, Park (Ronaldo 60), Rooney, van Nistelrooy.
Subs Not Used: Howard, Rossi.
Booked: van Nistelrooy, Smith, Fletcher, O'Shea.
Goals: Ronaldo 90.
Ref: A Wiley (Staffordshire).