The opening match of Group C for both sides could set the tone for their hopes of making it to the first end-of-year World Cup in the competition's long and illustrious history.
For the opening three matches in qualification for Qatar 2022 - which comes around after their campaign to reach Russia ended in playoff failure - Italy coach Roberto Mancini has called up a substantial 38-man squad, featuring several new faces who could be set to shine at the European Championship finals this summer.
Both Spezia's Matteo Ricci and Rafael Toloi, of Atalanta, have been selected for the first time - Brazil-born defender Toloi has just obtained clearance from FIFA in order to change nationality, taking advantage of his Italian heritage - and joined a diverse group at the Coverciano training facility, ahead of the visit of Northern Ireland on Thursday.
Among the call-ups from outside Serie A are three 'Parisians' - Alessandro Florenzi, Moise Kean and Marco Verratti - plus forward Vincenzo Grifo, of Bundesliga side Freiburg, as Mancini aims to get off to a flying start in Group C and also sift through the contenders for a place in his squad in June.
The former Lazio striker has won 15 of his 24 games in charge of Italy - with the Azzurri scoring 54 goals and conceding just 14 - and is expected to sign a contract extension in the coming weeks.
However, the former Manchester City manager's preparations were disrupted when the Milanese health authority banned Inter players from joining their national teams after four COVID-19 cases emerged in the Nerazzurri's squad. Assuming they return a series of negative tests, though, they have been given the all-clear to leave the second city.
Having not played for the last five months - and facing a particularly physical contest against Ian Baraclough's team - Mancini will want all of his key men to hit the ground running in a modest-looking section, also featuring neighbours Switzerland, as they begin their bid for a fifth global title.
One player who regrettably remains absent from the latest Azzurri selection is Roma's Nicolo Zaniolo, who is likely to miss out on Euro 2020 after his national coach confirmed that he would not be willing to take a gamble on the fitness of one of Calcio's brightest stars.
Zaniolo's most recent serious injury came in last September's Nations League clash with the Netherlands and, though he is expected to return to action next month, it appears too late for him to join the quest for continental glory this summer.
Italy have, in his absence, managed to seal a place in the final four of the Nations League next autumn, where they will meet old rivals Spain. Having topped a group including the Netherlands and Poland to get there, they will now be confident of taking a trip to the Middle East late next year.
Looking to bounce back from their playoff heartbreak in qualification for the Euros, Northern Ireland start their qualifying campaign in Parma on Thursday before taking on the USA in a Windsor Park friendly three days later.
Boss Ian Baraclough has called up Shayne Lavery, who played under the former Motherwell manager for the Under-21s, after eight goals in his last five games for Irish League leaders Linfield.
The in-form forward is one of six attacking options in Baraclough's first squad of what is set to be a testing campaign and joins Accrington Stanley striker Dion Charles in the Green and White Army's setup, after he was called up for the first time - having racked up 17 goals for the League One side this season.
Starting upon the long road to Qatar with a daunting task in Emilia-Romagna, 45th-ranked Northern Ireland have failed to win any of their last 10 games - though beat Bosnia on penalties - and know that only group winners are guaranteed progress to the finals, while the 10 runners-up will go through to the playoffs.
Despite their proud record of upsetting bigger nations - particularly on home turf - Northern Ireland have never won on Italian soil, with their only past victory over the Azzurri being a 2-1 home success on the way to the 1958 World Cup finals.
In fact, of their eight other historic encounters with the four-times world champions, they have lost six games and drawn two, so will be grateful for even a point this week to start their journey towards a potential fourth finals qualification.
Chelsea midfielder Jorginho and Inter Milan counterpart Nicolo Barella have been regular starters for Italy under Roberto Mancini, but the former has a knee injury and Barella was late joining up with the squad because of a COVID-19 outbreak at Inter Milan.
Fellow Inter pair Stefano Sensi and Alessandro Bastoni have been subject to restrictions too, but all three have now been allowed to leave Milan. Meanwhile, further issues affecting the Azzurri's midfield selection include an injury to versatile Roma midfielder Bryan Cristante.
Andrea Belotti and Ciro Immobile are the favourites for the central striker's role on Thursday, with in-form Lorenzo Insigne and Domenico Berardi potentially featuring out wide. Young forward Moise Kean, on loan to PSG from Everton this season, pulled out of the squad on Wednesday.
For Northern Ireland, Jamal Lewis is a major doubt due to a groin injury and the Newcastle United full-back did not train with the rest of the squad on Tuesday.
Manager Ian Baraclough is set to make a late decision on the defender's fitness, but will be relieved to have experienced Leicester City centre-back Jonny Evans, who played in the FA Cup on Sunday, available - though the stalwart defender did not train on Tuesday either.
Linfield forward Shayne Lavery has been called up and could feature at some stage, while uncapped Liverpool Under-23 goalkeeper Liam Hughes has also been added as back-up to first choice Bailey Peacock-Farrell, who has been short of first-team action at Burnley.
Hearts striker Liam Boyce is not expected to join up with his team-mates until later in the camp, as he awaits the birth of his second child, while skipper Steven Davis is set to equal Peter Shilton's British international caps record of 125.
Italy possible starting lineup:
Donnarumma; Emerson, Bonucci, Chiellini, Florenzi; Locatelli, Verratti, Barella; Insigne, Immobile, Chiesa
Northern Ireland possible starting lineup:
Peacock-Farrell; McNair, J. Evans, Cathcart; Dallas, Davis, Saville, C. Evans, Kennedy; Magennis, Lafferty
We say: Italy 2-0 Northern Ireland
Looking to blend some promising youngsters with the established old guard that failed to progress through the last World Cup qualifiers, Roberto Mancini has developed a consistent unit capable of pushing for major honours once more.
The Azzurri can take the first step towards doing so with a regulation win over Northern Ireland, who have seen the wind drop from their sails since failing to reach the Euros and are without a win inside 90 minutes for well over a year.