The former Stoke City boss will be attempting to bring an instant improvement to his nation on the international stage after their decline since his departure in 2020.
Match preview
When a near eight-and-a-half-year stint as Northern Ireland boss came to an end in April 2020, Michael O'Neill's exit was deemed to be an end of an era as he deservedly got his shot in English football with Stoke City.
However, after O'Neill failed to take the Potters back into the Premier League, the 53-year-old finds himself back in the Green and White Army dugout readying himself for his 73rd match in charge.
Having been handed a contract until 2028, this is deemed to be a long-term project, and patience will be required on the back of just six wins coming from 28 games under Ian Baraclough.
Their latest UEFA Nations League campaign was almost a disaster with Northern Ireland only avoiding finishing below Cyprus and having to participate in the relegation play-outs on goal difference.
Going forward, Northern Ireland have been presented with a favourable Euro 2024 qualifying group with Denmark, Finland, Slovenia, Kazakhstan and San Marino lying in front of them.
Nevertheless, they can ill-afford any slip-ups versus the underdogs of the group, who will view Thursday's match as an opportunity to record one of the most notable results in their history.
San Marino have not won an international fixture since 2004, and have not scored a goal against a European nation since losing 2-1 at home to Lithuania 12 months ago.
Nine goals were conceded in four fixtures versus Estonia and Malta in the Nations League without netting, although San Marino did draw 1-1 with St Lucia - a team 39 places above them in the FIFA World Rankings - in November.
Since 2008, these two nations have met on four occasions in World Cup qualifiers, Northern Ireland prevailing on each occasion by either a 3-0 or 4-0 scoreline.
San Marino form (all competitions):
L
L
D
L
D
L
Northern Ireland form (all competitions):
L
D
L
D
W
L
Team News
O'Neill's first Northern Ireland XI is difficult to call with Jonny Evans and a whole host of midfielders missing the game on Thursday.
A 4-4-2 may be deployed with Paddy McNair deputising in the centre of the pitch alongside George Saville, with Conor McMenamin getting an opportunity down the left flank.
O'Neill may also feel that this game represents the ideal chance for Dion Charles to finally end his wait for an international goal in what would be his 14th appearance.
The goalkeeper and back four could pick itself with Bailey Peacock-Farrell, Conor Bradley, Daniel Ballard, Craig Cathcart and Jamal Lewis the most likely combination.
Meanwhile, barring any fitness issues, San Marino boss Fabrizio Costantini could look to name a similar side to the one which impressed versus St Lucia at the back end of last year.
San Marino possible starting lineup:
Benedettini; Cevoli, Grandoni, Palazzi, Tosi, D'Addario; Capicchioni, Golinucci, Mularoni; Vitaioli, Rinaldi
Northern Ireland possible starting lineup:
Peacock-Farrell; Bradley, Ballard, Cathcart, Lewis; Whyte, McNair, Saville, McMenamin; Charles, Magennis
We say: San Marino 0-2 Northern Ireland
While this should theoretically be one of Northern Ireland's easiest fixtures of the group, it comes with the added pressure of being a must-win. Although the visitors should achieve that comfortably enough, do not expect the goals to flow as they normally do against San Marino.