The two sides won the Portuguese and Dutch top flights respectively last year, and will both be keen to get off the mark at the first time of asking.
In his first full campaign in professional management, Ruben Amorim guided Sporting Lisbon to the Primeira Liga title last season, breaking a 19-year drought for the capital side.
They achieved that goal by collecting 85 points from 34 league games, while only conceding 20 goals, and Os Leoes remained unbeaten until they were handed a narrow 4-3 loss by city rivals Benfica in the penultimate game, having already sealed the title by that point.
Amorim's men began their defence of the Portuguese top flight with three straight wins to start the season, defeating Vizela, Braga and Belenenses, but they have seen their form stall since then.
The winning run was put to an end by a relatively disappointing draw with Famalicao, as Joao Palhinha drew them level in the 82nd minute after a Nuno Mendes own goal saw them fall behind, but Os Leoes earned a more commendable point last time out, drawing 1-1 with fellow title-chasers Porto.
Upon their return to the Champions League, the 19-time Portuguese champions will be desperate to start with a win, but face a tough test against an Ajax side who are experienced on this stage.
Erik ten Hag's side find themselves in the group stage after winning the Eredivisie for the 35th time last year, cruising to the title with an eye-catching tally of 88 points, 14 ahead of second-placed PSV Eindhoven.
After coming within seconds of the Champions League final in the 2018-19 season, eventually being denied by a late Tottenham Hotspur comeback, the Dutch outfit fell into the Europa League knockout stage for the second straight campaign last time around, after finishing third in their Champions League group with seven points.
Ten Hag's men progressed to the final 16 of Europe's secondary competition with a 4-2 aggregate victory over Lille and went a stage further as goals from Dusan Tadic, Davy Klaassen and Brian Brobbey fired them to a 3-0 home win over Young Boys, before Tadic again got on the scoresheet alongside David Neres in Switzerland to seal a 5-0 aggregate victory.
De Godenzonen were unable to go any further than the quarter-finals though, as they eventually fell to a narrow 3-2 defeat at the hands of Italian outfit Roma, and they will now be keen to break back into the Champions League knockout stages after a two-year absence.
They come in on the back of a strong start to the domestic season, collecting 10 points from four games, as they most recently thrashed Vitesse 5-0 and picked up a 2-0 away win over PEC Zwolle thanks to a Sebastian Haller brace.
The Amsterdam outfit will now look to build on that with a victory to kick off the group stage, as they go in search of a top-two finish this time around.
Sporting Lisbon will be without captain Sebastian Coates, who will serve a suspension on Wednesday.
Meanwhile, star forward Pedro Goncalves could miss out through injury, after firing them to the title with 23 goals last season.
The departure of promising left-back Nuno Mendes should see Wolverhampton Wanderers loanee Ruben Vinagre line up on the left-hand side, while fellow new signing Ricardo Esgaio should again occupy the other flank.
The line will be led by Sebastian Haller, who has registered 17 goals and eight assists in 28 appearances in all competitions since arriving from West Ham United.
He is supported by plenty of attacking talent, with key man Dusan Tadic occupying a flank, while Dutch star Steven Berghuis was poached from rivals Feyenoord in the summer.
Sporting Lisbon possible starting lineup:
Adan; Feddal, Inacio, Reis; Esgaio, Palhinha, Nunes, Vinagre; Cabral, Paulinho, Santos
Ajax possible starting lineup:
Stekelenburg; Mazraoui, Timber, Martinez, Blind; Gravenberch, Alvarez; Antony, Berghuis, Tadic; Haller
We say: Sporting Lisbon 1-2 Ajax
We certainly see this being a closely-fought encounter, between two sides who excelled on the domestic scene last season.
Given Sporting could be playing without both their key centre-back and key attacker, we give the narrow edge to the visitors, as they arrive in Lisbon at somewhat of a good time, although it will certainly not be a routine victory for ten Hag's men.