City were held to a draw last time out by Atalanta but the Manchester club have been pretty dominant in this year's group stage thus far, scoring 11 goals in their opening four group games.
Their free-flowing attack and home advantage makes them heavy favourites against a Shakhtar side who have lost on both of their previous visits to the Etihad, conceding eight goals without reply.
Gabriel Jesus caused the Ukrainians all sorts of issues last season and he is expected to start on Tuesday, while the pace and creativity of Raheem Sterling and Riyad Mahrez will ensure that City get plenty of good goalscoring opportunities.
City enter the game on a hot streak of form in this competition, winning their last six at home and 11 of their last 13 at the Eithad in the group stage.
Luis Castro's men recorded an important 4-1 win over FC Lviv in domestic action on Friday but the result came at a cost as Junior Moraes, who scored a hat-trick in that game, picked up an injury that is expected to rule him out of Tuesday's game.
Shakhtar will be hoping for a result against City as they look to keep their hopes of progressing to the last 16 alive and the stats suggest that they will get chances to score, with City failing to keep a clean sheet in their last five games across all competitions.
The Miners showed great fight against Dinamo Zagreb in their last group game, coming from behind to draw 3-3 deep into injury time but the game also showed their potential for defensive lapses at key times and their indiscipline.
Castro's men have had a player dismissed in four of their last six matches and they will need to retain their full complement against a City team who will be looking to pass them off the park and dominate proceedings from within their opponents' half.
Manchester City recent form: WWWD
Manchester City recent form (all competitions): WWWDLW
Shakhtar Donetsk recent form: LWDD
Shakhtar Donetsk recent form (all competitions): DDLWDWW
Manchester City remain without the services of long-term absentees Leroy Sane, Aymeric Laporte and Oleksandr Zinchenko, while Sergio Aguero, David Silva and Rodri all went off with knocks against Chelsea.
Of the three that were injured on Saturday, Aguero is the most likely to miss out on Tuesday, with Gabriel Jesus expected to start in his absence.
Bernardo Silva could well return after serving a suspension at the weekend, while Guardiola may look to rotate some of his defenders with certain players close to picking up suspensions for their final group game with Dinamo Zagreb.
Manchester City possible starting lineup:
Ederson; Walker, Otamendi, Stones, Mendy; Gundogan, Rodri, De Bruyne; Mahrez, Jesus, Sterling
We say: Manchester City 4-1 Shakhtar Donetsk
Manchester City should have far too much on Tuesday for a Shakhtar Donetsk team without a number of first-team regulars.