The hosts took over half an hour to get going but five goals in under 30 minutes saw off the minnows and set-up a fourth round clash with Coventry.
Despite the scoreline Nuneaton deserve every credit. Their players put a spirited performance on and their 5,000 fans offered magnificent support throughout the 90 minutes.
With the Middlesborough players, and manager Steve McClaren, under tremendous pressure following a dismal run of results this was a vital win.
Whether it can lift them enough to get their Premiership campaign back on track against Wigan on Saturday remains to be seen. But at least Middlesbrough got into the scoring act and gave their fans something to cheer.
But the Nuneaton players stayed on the field long after the home team had disappeared down the tunnel. The non-league players had every right to soak up the atmosphere, for this was a special night for the Midlands side who had battled through the rounds for a money-spinning high at the Riverside Stadium.
Gez Murphy, who scored a dramatic last-minute penalty to force the replay, nearly gave Nuneaton an early lead.
Murphy's big chance came after just six minutes but he was thwarted by a brilliant one handed save low down from Brad Jones.
The Nuneaton fans taunted Middlesborough with a "We Want Seven" chant early in the game, but found their team two down at the break.
Home skipper Chris Riggott relieved the tension for the home side when he scored his first goal of the season after 34 minutes, lobbing the ball over Nuneaton shot-stopper Darren Acton.
Middlesborough were awarded a penalty two minutes before the interval when Stuart Whittaker brought down Gaizka Mendieta. The visitors were not happy about the decision but it gave Yakubu his 13th goal of the season.
It was then the turn of the home fans to chant "We Want Seven".
Early in the second half Mendieta crashed a fierce shot into the side-netting before full-back Stuart Parnaby scored his first-ever Middlesbrough goal with a fierce 20-yard shot.
After 58 minutes Yakubu beat the advancing Acton and drove the ball into the far corner of the net to make it four.
The fifth goal followed five minutes later when Mark Viduka pounced on a loose ball in the penalty area and gave Acton no chance.
Nuneaton were being out-classed at this stage but, to their credit, they never gave up and were rewarded with a Murphy goal in the 71st minute.
The lively Murphy then had the satisfaction of scoring another goal in the closing minutes.
Middlesbrough substitute Ray Parlour brought down Murphy in the penalty area and the striker picked himself up to beat Jones with his spot-kick.