Holders United, who lost to AC Milan on Tuesday, travel to face struggling Premier League rivals Southampton on Saturday while Arsenal, dumped out by Bayern Munich on Wednesday, face a tough trip to buoyant Bolton Wanderers.
On Sunday the only survivors from outside the top flight, Leicester City, will come face to face with former striker Paul Dickov at Blackburn Rovers and the last-eight action concludes with Newcastle United's home tie against Tottenham Hotspur.
United and Arsenal fans, spoiled in recent years by epic title battles and extended runs in the Champions League, may have nothing but a scrap for the league runners-up spot to look forward to should their teams fail this weekend.
Barring an unlikely capitulation by runaway leaders Chelsea in the league, the FA Cup is now their only hope of salvaging some pride out of humbling seasons, but they both face dangerous hurdles.
Bolton, who moved up to sixth in the league with a 1-0 victory over Manchester City on Monday, have already inflicted considerable damage on the Gunners this season.
Their 1-0 victory over the champions at the Reebok Stadium in January left Arsene Wenger virtually conceding the title to Chelsea and they will relish piling more misery on the Frenchman who will be without injured striker Thierry Henry.
Bolton boss Sam Allardyce has not always made the FA Cup a priority but 'Big Sam' has set his sights on taking the club to its first final since 1958.
Bolton's Kevin Nolan summed up the mood.
"The manager's been drumming it in how much he wants to win it, and with any luck we'll have a full house which will be like an extra man," said the Liverpool-born midfielder.
WELCOME BREAK
There will also be a capacity crowd at St Mary's stadium where Harry Redknapp's Southampton can take a welcome break from the stress of their fight against relegation.
Despite still being in the bottom three the Saints have not been beaten at home since September and will have nothing to lose as they try and beat United in the Cup for the third time, the most memorable being in the 1976 final.
Tottenham, who won the last of their eight FA Cups in 1991, are desperate to get their hands on some silverware as they begin a new era under Dutch coach Martin Jol.
The London club have made steady progress since Jol took over from Jacques Santini in November, although a trip to rapidly-improving Newcastle was not what he would have wanted from the sixth round draw.
"At first I thought why did it have to be Newcastle away?" he said. "But you must beat two or three of the top teams to reach the final."
Newcastle's season has finally shaken off the hangover of Bobby Robson's sacking and a 3-1 victory over Olympiakos on Thursday put them on course for the UEFA Cup quarter-finals.
Victory over Tottenham would have the club's success-starved fans dreaming of a first FA Cup triumph since 1955.
Leicester have reached the quarter-finals for only the second time in 23 years, although a trip to the semi-final may be beyond a club who have fallen on hard times since dropping out of the Premier League last season.
