Los Blancos suffered a shock first defeat of the domestic season at the weekend and need to quickly pick themselves up against a Shakhtar side unbeaten in five.
After winning the Champions League in three successive seasons between 2016 and 2018, Madrid have now exited the competition in the last-16 stage in back-to-back campaigns.
Last season's early exit at the hands of Manchester City was a tough one to take, but the blow was softened by a first La Liga title in three years.
As ever with Madrid, the target this term will be a clean sweep of honours - La Liga, Champions League and Copa del Rey - but they have made a mixed start to 2020-21 overall.
Zinedine Zidane's drew 0-0 with Real Sociedad in their opening league match and lost 1-0 at home to newly-promoted Cadiz at the weekend, bookending three wins in a row.
Next up for the champions in the league is the small matter of Barcelona away on Saturday, but first they have this potentially tricky tie against Shakhtar to navigate.
The Miners won their domestic league for a fourth season in a row last time out but have been slow off the mark this term, drawing three of their opening six matches.
However, they thumped Lviv 5-1 last time out in perfect preparation for this trip to the Santiago Bernabeu, where they will be looking to pull off a shock victory.
Madrid have not lost in their last eight meetings at home to Ukrainian opposition since 1999, and won both games against Shakhtar when they last met in the 2015-16 group stage.
A good omen for Shakhtar, perhaps, is that they have lost on matchday one in only two of their last seven Champions League campaigns, albeit with one of those defeats coming against Madrid.
In a group that also contains Inter Milan and Borussia Monchengladbach, Los Blancos will know that they cannot afford to slip up in this opening fixture.
Real Madrid form (all competitions): DWWWL
Shakhtar Donetsk form (all competitions): LDDWDW
That could be a big blow for the visitors as Moraes has had a direct hand in eight goals in 12 Champions League games - the most of any player for the club since September 2018.
Real Madrid possible starting lineup:
Courtois; Nacho, Varane, Militao, Mendy; Valverde, Casemiro, Kroos; Rodrygo, Jovic, Vinicius
Shakhtar Donetsk possible starting lineup:
Trubin; Dodo, Khocholava, Bondar, Korniienko; Maycon, Patrick; Marlos, Kovalenko, Taison; Dentinho
We say: Real Madrid 2-0 Shakhtar Donetsk
Madrid's focus may well be elsewhere, with a huge league trip to Barcelona on the horizon, but Zidane will know the importance of bouncing back from defeat last time out.
Under-strength Shakhtar have struggled to get wins on the board domestically this term and, on the continent, have conceded at least one goal in each of their last 22 Champions League games.
Even accounting for some changes, Zidane's men should have more than enough firepower to get the job done in this opening Group B clash.