The Italian outfit are forced to play their home games 50 kilometres away in Milan with their own stadium being redeveloped but will hope that they still have a distinct advantage in their first 'home' Champions League outing.
Atalanta's Champions League debut quickly turned from a dream into a nightmare on matchday one as they slumped to a chastening 4-0 defeat at the hands of Dinamo Zagreb in Croatia.
On paper it looked like a kind welcome to Europe's elite competition, with Zagreb having lost each of their previous 11 Champions League group games, but it was an entirely one-sided affair which has left Gian Piero Gasperini's side with a mountain to climb if they are to challenge for a knockout place.
Gasperini has already admitted that there is "no margin for error" in this match with back-to-back games against Manchester City to follow, and defeat on Tuesday could leave them hoping for a third successive Europa League campaign at best.
The San Siro has, of course, seen many famous European nights and, while there is sure to be some level of disappointment at such a big match in Atalanta's history not taking place in Bergamo, at least 25,000 fans are still expected to make the 45-minute drive to Milan, which is more than the capacity of their home Gewiss Stadium.
There will be plenty of Atalanta noise regardless of the more unfamiliar surroundings, then, but even if it feels more like an away game then that could still suit the Italians - in Europe's top five leagues only Man City have won more away top-flight games in 2019 than Atalanta's tally of 10.
The most recent of those was a highly-impressive 2-0 triumph at Roma last Wednesday, continuing a return to form since that Zagreb defeat which has also seen them score two late goals to salvage a draw against Fiorentina and blow Sassuolo away with a first-half blitz on Saturday.
It will take a lot to intimidate Shakhtar when it comes to domestic form, though, with the Ukrainian outfit well on course for a fourth straight title having stormed into a 10-point lead after just nine games of the new season.
Luis Castro's side have been faultless in the league so far with nine wins from nine, scoring 28 goals and conceding just six in the process.
Such impressive form does not only date back to the start of this campaign, though; Shakhtar's league winning run now stands at 11, while they are unbeaten in the top flight since August 2018, a run of 38 matches.
The matchday one defeat to Man City did not come as a surprise, but the ease with which the English champions ran out 3-0 winners in Ukraine will have fired another reminder that this Shakhtar side are still some way short of translating that domestic dominance onto the European stage.
Nevertheless, they will fancy their chances of competing for their first points in Group C this season and may not get many better opportunities to record what would only be a second win on Italian soil from 12 visits.
Atalanta form: LWLDWW
Shakhtar form: WWWLWW
Luis Muriel has missed Atalanta's last two games due to tonsilitis and remains a doubt for this match, although Gasperini will be hopeful of having the Colombian fit to start alongside compatriot Duvan Zapata, who has five goals in his last five league games.
The only other injury concern for the hosts is captain Papu Gomez, who picked up a minor knock at the weekend but should recover in time to start this match.
Gomez has experience of Ukrainian football from his time with Metalist Kharkiv, when he played alongside current Shakhtar player Marlos.
Midfielder Ruslan Malinovskyi may also have a point to prove having come through the ranks at Shakhtar and been on their books from 2011 to 2017 without ever making a first-team appearance for the club.
The visitors have no major absentees for this match, with Andriy Totovytsky the only player guaranteed to miss the contest through injury.
Atalanta will need to keep a close eye on Junior Moraes, whose goal in the win over Vorskla Poltava on Friday took him to eight in 11 games this season, not to mention four assists.
Atalanta possible starting lineup:
Gollini; Toloi, Palomino, Masiello; Hateboer, Freuler, De Roon, Castagne; Gomez; Ilicic, Zapata
Shakhtar possible starting lineup:
Pyatov; Bolbat, Kryvtsov, Matviyenko, Ismaily; Marlos, Stepanenko, Alan Patrick; Solomon, Moraes, Taison
We say: Atalanta 2-2 Shakhtar
This match is a difficult one to call, with neither side doing themselves justice on matchday one. Atalanta in particular will want a reaction to their defeat for their Champions League home debut, but Shakhtar have enough attacking firepower to come away from the game with something.