Mircea Lucescu's side were thumped 4-0 in Germany on matchday three in Group A, their joint heaviest defeat in the competition and Leverkusen's biggest win in the Champions League.
The result left Shakhtar in third place, two points adrift of Leverkusen in second and three behind leaders Manchester United.
After winning 2-0 at Real Sociedad in their opening game Shakhtar drew 1-1 with United at home before the comprehensive defeat to Leverkusen a fortnight ago.
Lucescu's charges have made an indifferent start to the defence of their Ukrainian Premier League title, currently lying second in the table, two points shy of leaders Metalist, having dropped 13 points from 15 matches, already two more than in the whole of last season.
They come into the game on the back of a disappointing 2-0 away defeat at Volyn, a result that ended a run of three consecutive victories in the league.
The last time Shakhtar hosted German opponents was in last season's round of 16, eventual runners-up Borussia Dortmund coming away with a 2-2 draw before sealing their place in the last eight with a 3-0 win in Germany.
Overall, Shakhtar have lost just once at home against German clubs, while Leverkusen have won two and lost three of their five trips to Ukraine.
Their most recent visit, in last season's Europa League group stage, ended in a 2-0 defeat to Metalist, a far cry from their visit to the same opponents in the same competition two years earlier, when they returned to Germany with a 4-0 victory.
Sami Hyypia's side have recovered well since a 4-2 defeat at Old Trafford on matchday one, seeing off Real Sociedad 2-1 at home in the next game before the win over Shakhtar.
If they prevail on Tuesday, it will be the first time Leverkusen have won three times in the same Champions League campaign since 2002, although they head into the match having lost their last league fixture, going down 1-0 at bottom club Eintracht Braunschweig on Saturday.
That was just their second league defeat of a season, which sees them in third place after 11 matches, four points adrift of leaders Bayern Munich.
Leverkusen's top scorer Stefan Kiessling is expected to return after being rested from the starting XI on Saturday, while Emir Spahic missed that match with a back injury suffered on the eve of the game.
Levin Oztunali returned to training in the week after recovering from an ankle problem, while Stefan Reinartz has missed the last three matches with a heel injury.
For Shakhtar, Wellington Nem made his first-team debut in the 4-0 league win over Zorya at the end of October following knee surgery in August, but the Brazilian will not be available on Tuesday as he was not included in their Champions League squad.
