A Louis Saha penalty, a spectacular Cristiano Ronaldo free-kick and a second-half header from Nemanja Vidic gave United a three point lead over Chelsea, who face a trip across London to Tottenham on Sunday.
In the day’s other games, a home defeat to Premiership newcomers Sheffield United pushed Newcastle into the relegation zone.
Liverpool’s recent revival gathered pace with Dutch striker Dirk Kuyt grabbing a double in a 2-0 win over Reading, although Rafa Benitez’s men remain 11 points adrift of the leaders.
Ferguson, who celebrates two decades at Old Trafford on Monday, insisted there would be no pre-match presentation or guard of honour.
But his players ensured the occasion was marked in fitting style.
With barely two minutes gone, Wayne Rooney burst into the Portsmouth box and won a penalty that Louis Saha converted.
Seven minutes later, a foul on the French striker led to a free-kick, which Ronaldo rifled in from 30 yards.
Vidic made the points absolutely safe in the 66th-minute, heading Gary Neville’s cross powerfully past David James.
Ferguson said: “Obviously, it is an incredible statistic. Twenty years at any football club is amazing. It seems to have flown in and I don’t know where the years have gone.
“But the only thing you can do is look forward as we always do here and hopefully there are a few good years ahead.”
Danny Webber was Sheffield United’s hero with the 68th-minute strike that gave Neil Warnock’s side victory over Newcastle at St James’ Park.
It was also a good day for Watford, who joined Sheffield Utd in moving out of the drop zone by beating Middlesbrough 2-0, their first win since returning to the top flight.
Charlton’s spirits were also raised by a 1-0 win over Manchester City, although Iain Dowie’s side remain bottom because of their rivals’ victories.
Third-placed Bolton slumped to a home defeat for the second weekend in a row when Scotland striker Lee McCulloch scored a superb winner for Wigan with nine minutes left at the Reebok Stadium.
Fulham maintained their jinx over Everton, a 1-0 victory ensuring that the Merseysiders have now gone 40 years since they last earned a point at Craven Cottage.