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With Edinson Cavani also absent from the matchday squad and Marcus Rashford on the bench, United's attack does not feature an out-and-out striker, with Bruno Fernandes, Jadon Sancho, Anthony Elanga and Paul Pogba set to operate in forward areas at the Etihad Stadium. Defenders Raphael Varane and Luke Shaw have been sidelined after testing positive for coronavirus.
"We have two Covid cases with Rafa and Luke, and Cristiano has some problems with his hip flexor again on Friday," United's interim boss Rangnick told Sky Sports.
Manchester City will have a similarly fluid front line, with Phil Foden, Jack Grealish, Riyad Mahrez and Bernardo Silva in the hosts' attack, but they are missing injured centre-back Ruben Dias, in a game you can watch live on Sky Sports Premier League from 4pm; kick-off 4.30pm.
This will be just the second Premier League game 37-year-old Ronaldo has missed since rejoining United this season, however, he has scored just one goal in his last 10 appearances.
Keane: Something doesn't add up
Speaking ahead of kick-off on Super Sunday, Sky Sports pundit Roy Keane believes something about Ronaldo's absence "doesn't add up" but expects United to manage without him.
"I'll expect Manchester United to play wide and they've got the pace, while I expect Fernandes to drop in and pick out the runners," he said.
"It's a surprise to hear Ronaldo has a hip injury but United have pace, quality. They still have important players and they still have to come out and play with pride. Elanga is a really good, positive player who makes intelligent runs.
"There seems to be more to the Ronaldo story when a manager comes out and talks about a hip flexor. I don't get it. We talk about Ronaldo being a machine and very rarely getting injured but every now and again he comes out with that... a hip flexor? It doesn't add up to me."
Fellow Sky Sports pundit Gary Neville added Ronaldo's forced absence may not be as big a blow as it may seem, given the style of play United are likely to employ against their neighbours - although he had expected Rashford to start up front in Ronaldo's place.
"United over the last three or four years were a counter-attack team, really comfortable sitting back punching out on the break and that will be exactly the same today," he said.
"Cristiano not being in the team, I could never say it's a positive, but I don't see it as a big loss that I might do in other games."
Former striker Andy Cole - who played up front for both United and City - believes Pep Guardiola's defenders will be pleased by the news Ronaldo is not playing.
"You can talk about his age and what people perceive him to be contributing in games but if he's not playing, as a centre-half, I'd be a lot happier," Cole told Sky Sports News.
"You know if he gets half a chance there's a good chance he'll take it. You don't get as many goals as he has throughout his career if you don't know what you're doing when you get in the box."
However, Sky Sports' Paul Merson had said on Soccer Saturday he believed the visitors would have a better chance of winning at the Etihad Stadium if Ronaldo was dropped.
"I'd play [Marcus] Rashford and [Anthony] Elanga," said Merson. "If they've got any chance of winning this game, they have to play on the counter-attack with plenty of pace, skill and energy.
"Personally, I'd leave Ronaldo out of this game. Against Watford, they dominated the game and had something like 80 per cent possession, but they're not going to have the ball as much against City.
"How many times are they going to be in City's half dominating the ball? If you're John Stones or Aymeric Laporte, they would rather play against Ronaldo than mark someone like Rashford. They don't want to play up against pace."
Manchester derby preview podcast: Will United upset the odds? And who makes our combined XI
In the latest Football Essential Podcast, host Ron Walker is joined by Sky Sports senior football journalist Charlotte Marsh, Sky Sports News' Ben Ransom and Sky Sports Football data editor Adam Smith ahead of a weekend where the eyes of the Premier League will be on Manchester.
PART ONE | How do Manchester United turn the tide from such a woeful defeat at Old Trafford earlier in the season? Could this be a 'statement win' for City, and perhaps a 'statement performance' from £100m man Jack Grealish too? Then again, could Riyad Mahrez prove the difference?
PART TWO | Who needs the victory more? Will Manchester United's April, facing City and Liverpool, hold the keys to the title race, and will they make it into the top four? Can City lift the treble, and are they better placed than Liverpool to rack up a trophy haul this season? Plus, our combined XI - including one big absentee.
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