Zinedine Zidane's side are currently second in Group B, three points clear of third-placed Shakhtar, meaning that a victory in this game would see them advance to the knockout round of the competition.
Shakhtar are still in the argument when it comes to qualification for the round of 16, but they will need to pick up a positive result on Tuesday night in order to stay alive heading into their final game with Inter Milan.
The Ukrainian giants recorded an incredible 3-2 win over Madrid in the reverse game at the Bernabeu on October 21 before picking up a welcome point at home to Inter in their second group fixture.
Shakhtar's last two results have been incredibly disappointing, though, suffering a 6-0 home defeat to Borussia Monchengladbach on November 3 before losing the reverse game in Germany 4-0 last week.
All things considered, securing third in the section would be seen as a huge positive, particularly considering the presence of Inter in the group. Luis Castro's side have two tough games to come, however, and will not exactly be full of confidence due to their result results.
The 13-time Ukrainian champions did pick up an important domestic win over Dnipro-1 on Saturday, though, to leave themselves second in the table behind Dynamo Kiev.
Madrid, meanwhile, will enter Tuesday's match off the back of a shock home defeat by Alaves in La Liga. Casemiro halved the deficit in the latter stages of the contest, but the visitors held on to record a surprise 2-1 win courtesy of goals from former Premier League strikers Lucas Perez and Joselu.
Los Blancos remain fourth in La Liga, six points off leaders Real Sociedad, but they cannot afford to dwell on the disappointment as they switch their attention back to the Champions League.
Zidane's side only picked up one point from their first two group games against Shakhtar and Gladbach but then managed to record back-to-back victories over Inter, including an impressive 2-0 success at San Siro.
As mentioned, a win on Tuesday would see Madrid advance to the last-16 stage of the Champions League and then potentially battle Gladbach for first position at the Alfredo Di Stefano Stadium on December 9.
Los Blancos have actually lost in the round of 16 in the last two seasons and will be desperate to advance deep into the competition this term but inconsistency has been a real problem in 2020-21.
Shakhtar Donetsk Champions League form: DLWDLL
Shakhtar Donetsk form (all competitions): WLWDLW
Real Madrid Champions League form: LLLDWW
Real Madrid form (all competitions): WWLDWL
Junior Moraes was not involved in the clash with Dnipro-1 on Saturday but should return to the starting XI for this match, while Tete and Manor Solomon are likely to keep their spots in the wide positions.
Andriy Pyatov was also left out of Shakhtar's domestic clash at the weekend, but the 36-year-old is expected to return for this game as the home side look to recover from two heavy losses in the competition.
Los Blancos are also unlikely to be able to call upon Eden Hazard as the Belgium international limped out of the defeat at Alaves on Saturday with a muscular issue.
Shakhtar Donetsk possible starting lineup:
Pyatov; Dodo, Bondar, Matvienko, Cipriano; Maycon, Antonio; Tete, Marlos, Solomon; Moraes
Real Madrid possible starting lineup:
Courtois; Vazquez, Varane, Nacho, Mendy; Kroos, Casemiro, Odegaard; Vinicius, Benzema, Rodrygo
We say: Shakhtar Donetsk 1-2 Real Madrid
Madrid will be determined to bounce back from Saturday's loss to Alaves, and the Spanish champions will also be hoping to gain some revenge on Shakhtar. There is no question that the home side are capable of making it a tricky contest, but we fancy Zidane's side to pick up all three points.