The home side will enter this match off the back of a 4-0 defeat to Eintracht Frankfurt in the Bundesliga, while Ukrainian giants Shakhtar recorded a 1-0 victory over Rukh Vynnyky in their last league fixture.
Match preview
Leipzig's 2022-23 Bundesliga campaign started away to Stuttgart on August 7, with the two teams playing out a 1-1 draw, and they have played a further five times across two competitions since then, including an 8-0 victory over Teutonia Ottensen in the German Cup.
Domenico Tedesco's side have only won once in the league this term, though, which came at home to Wolfsburg at the end of August.
Leipzig will enter their Champions League opener off the back of a 4-0 loss at Frankfurt on Saturday, and they now have a very tough run of matches, facing Borussia Dortmund and Borussia Monchengladbach in the league ahead of the international break, in addition to Shakhtar and Real Madrid in Europe.
Alongside Shakhtar and Real Madrid, Celtic are also present in Leipzig's section; Los Blancos will be the favourites to top Group F, but second spot looks to be extremely open, and it will be fascinating to see how the section unfolds over the next couple of months.
Leipzig failed to make it through the group stage of last season's European Cup, ultimately transferring to the Europa League, and they reached the semi-finals of the competition before losing to Rangers.
Shakhtar, meanwhile, will enter this match off the back of a 1-0 win over Rukh Vynnyky on Friday, which has left them second in their domestic table, boasting seven points from three matches.
The Ukrainian champions failed bottom of their Champions League group last season, but they did make it to the knockout round in 2017-18, losing to Roma in the round of 16.
Shakhtar also made the quarter-finals in 2010-11, losing to Barcelona, but it will take a big effort for them to advance through this particular section.
The team's next two games are likely to be crucial when it comes to their chances of making it through the group, as their next fixture after this one is at home to Celtic on September 14.
Igor Jovicevic's side have not conceded a single goal in the league this season, which should mean that confidence is high, especially as they are taking on a Leipzig side that lost by four on Saturday.
RB Leipzig form (all competitions):
Shakhtar Donetsk form (all competitions):
Team News
Leipzig were stunned by Frankfurt on Saturday, but head coach Tedesco is expected to resist the temptation to shuffle his pack for the Champions League contest with Shakhtar.
Dani Olmo is expected to miss out with the injury that he picked up against Frankfurt, so Dominik Szoboszlai should come in for a start, while Emil Forsberg is expected to be introduced in central midfield.
There are unlikely to be any changes further forward, though, with Timo Werner and Christopher Nkunku again set to feature as the front two.
Lukas Klostermann and Yussuf Poulsen remain on the sidelines for the hosts through injury.
Shakhtar, meanwhile, have not reported any fresh concerns from their league win last time out, so head coach Jovicevic could keep faith with the same XI for this clash.
Mykhailo Mudryk was sent off on Friday but will be available for this European contest, and the 21-year-old should again feature in a wide position.
Danylo Sikan is yet to find the back of the net in three appearances this season, but the Ukrainian is again expected to lead the line for the visitors here.
RB Leipzig possible starting lineup:
Gulacsi; Simakan, Orban, Gvardiol; Henrichs, Laimer, Forsberg, Raum; Szoboszlai; Nkunku, Werner
Shakhtar Donetsk possible starting lineup:
Trubin; Mykhaylichenko, Matvienko, Bondar, Konoplya; Mudryk, Bondarenko, Stepanenko, Sudakov, Petryak; Sikan
We say: RB Leipzig 2-1 Shakhtar Donetsk
Leipzig will be determined to bounce back from their league defeat on Saturday, and we are backing the German side to triumph. Shakhtar certainly have the quality to cause problems, but Leipzig should just have enough to pick up an important three points in their section opener.