Cup holders Pompey sent packing by Swans
Berbatov, who left London for United in August, outpaced the defence after 36 minutes, latching on to a lofted pass from Michael Carrick and firing past goalkeeper Ben Alnwick before celebrating the goal in front of the Spurs fans.
That put the home side ahead just after a deflected long range shot from Paul Scholes had cancelled out Roman Pavlyuchenko's fifth minute opener for Tottenham.
Championship Swansea City had earlier scored the day's biggest upset when they knocked out holders Portsmouth with a deserved 2-0 win at Fratton Park.
Portsmouth, who beat Cardiff City in the Cup final in May, had no answers against another Welsh side, Swansea winning with first half goals from Nathan Dyer, on loan from Portsmouth's arch-rivals Southampton, and a penalty from Jason Scotland.
Portsmouth manager Tony Adams, who took over from Cup-winning coach Harry Redknapp when he moved to Spurs in October, could not hide his disappointment after his side had been outplayed.
"It is not nice going out, full stop," Adams said.
"It doesn't matter whether you're the holders. When you are out-fought and outplayed for 45 minutes then you are always likely to be dumped out of the Cup."
There was little room for FA Cup romance elsewhere with none of the other unfancied teams managing upset victories.
Minor League Kettering Town came close to achieving a draw against Premier League Fulham before Andrew Johnson and Bobby Zamora scored late goals to give the visitors a 4-2 win while Championship side Doncaster Rovers held Premier League high flyers Aston Villa to a 0-0 draw.
Along with Sunday's Liverpool v Everton clash, the United-Spurs match was the highlight of the fourth round with Redknapp, whose Portsmouth side beat United in the FA Cup at Old Trafford last season, looking for his fourth career FA Cup victory over United.
United, struggling with an injury crisis and chasing four trophies, ran out fairly comfortable winners in the end against a Spurs side struggling at the wrong end of the Premier League.
Apart from a bright start and a late fightback at the end, the visitors rarely looked like salvaging much from the game as United dominated for long periods.
Pavlyuchenko's superb opening goal -- a glancing header from a Tom Huddlestone cross -- gave Spurs a surprise early lead.
However, United soon took control and Carlo Tevez went close twice, first being denied by the bar and then by a stunning save from Alnwick, playing only his second match for Spurs in place of Brazilian Heurelho Gomes.
The sides are due to meet again in the League Cup final at Wembley Stadium on March 1.
Apart from Portsmouth and Spurs, none of the other Premier League teams involved on Saturday lost with