The clash in West Yorkshire will see former Leeds midfielder Gary Speed - a player synonymous with their Division One title-winning season in 1992 - return to Elland Road as manager of Sheffield United having got the job in the wake of Kevin Blackwell's sacking last month.
Blackwell was removed from his post after only two league fixtures, making way for 41-year-old Speed to take up his first job in management.
He and Leeds boss Simon Grayson were team-mates at Elland Road at the beginning of their playing careers but their friendship will be suspended on Saturday as Grayson's squad bid to finish the demanding sequence of three successive derbies with a third home win.
Leeds have averaged crowds of around 26,000 for their Championship fixtures so far but the crowd for Sheffield United's visit is set to vastly exceed that figure.
The clubs' last meeting came in April 2006, ending in a 1-1 draw at Bramall Lane.
Speaking this week, chairman Ken Bates said: "We've already sold 28,000 tickets and we're expecting that to go into the mid 30s. That's why we opened the upper tier (of Elland Road's East Stand) and I'm delighted we have.
"Hopefully the crowd might go over 35,000 and there's no doubt that there's a real buzz in the city at the moment. It's very supportive of the club."
Leeds have made a stronger start to the Championship season than Sheffield United, who lost 4-0 at home to Scunthorpe United on Tuesday evening while Grayson's players were suffering an equally bad defeat at Barnsley.
Almost 7,000 Leeds supporters made the trip to Oakwell, a huge figure which maintained United's tradition of selling out the allocations they receive at away grounds.
Bates was highly critical of the 5-2 midweek defeat. "The players have to prove that they're worthy of that support," he said. "But I'm sure they will. We all have bad days."