United, the runaway Barclays Premier League leaders and 19 points clear of fourth-placed Chelsea, last won the FA Cup in 2004.
Since 2007, the Blues have dominated the competition with four wins in six years, while interim manager Rafael Benitez lifted the trophy with Liverpool in 2006.
Following the highs of Wembley and Munich last May, Chelsea are enduring a torrid 2012/13 season and became the first Champions League holders to exit at the group stage last November.
The Blues lost their opening last-16 Europa League fixture with Steaua Bucharest on Thursday night and Benitez is pleased to have a swift change of focus with a key fixture against fierce rivals.
"It's a positive. It's good and it's a challenge for us," he said. "In terms of the focus of the players, it's good. We have an opportunity very quickly to change things.
"It's a good competition, a very exciting competition and Chelsea, as a club and as a team, have been doing really well. Hopefully we can carry on doing well after this game. That means that we will be through."
Bar the third-round defeat of Southampton, so far this season, the FA Cup has not been one of solace for Chelsea or Benitez.
The Blues needed a replay to defeat npower League One side Brentford, then claimed a 2-0 win at Middlesbrough in a fifth-round tie overshadowed by comments made by Benitez.
The Spaniard hit back at his continual barracking by the club's supporters, telling them to use their energies to support the team and criticising the decision to name him 'interim manager', rather than just 'manager'.
It was an impassioned rant from the former Liverpool boss, reminiscent of those provoked by his frosty relationship with United manager Sir Alex Ferguson.
Benitez will renew hostilities with Ferguson at Old Trafford, where the hosts will be looking to prove a point following their Champions League elimination to Jose Mourinho's Real Madrid in midweek.
But Benitez would not be drawn on the nature of his relationship with Ferguson.
"I am a manager and I just concentrate on doing my job," he said, before adding that he will not be joining his United counterpart for a glass of red wine post-match.
"We know that he has a good team so this will be a very difficult game. That is normal. When you're running a top side and you're playing against top sides, it's always difficult."
Given the proximity of the fixtures - Thursday's second leg with Steaua will be Chelsea's third in eight days - Benitez is almost certain to rotate his squad.
John Obi Mikel made his fourth appearance since returning victorious from the African Nations Cup and the Nigeria midfielder is targeting further success in a competition in which he has an extensive medal collection.
"We've earned the right to say that it's our cup," Mikel told FATV.
"I've won it four times and I'm still hungry for it. I still want to win five, six, seven times.
"I still want to win trophies for this club and new players want to put hands on one of these trophies."
United are the obstacle in Mikel and Chelsea's way.
The 25-year-old added: "It's never an easy game. We've earned the right to be there, to play them at Old Trafford.
"It's a game that we have to look forward to. As a player these are the kind of games you want to be involved in."