Both teams go into the match off the back of defeats at the weekend, and having been drawn alongside Barcelona and PSV Eindhoven too, a poor start could prove costly for their European campaigns.
It has been six years since the three-time kings of Europe have featured in the Champions League, so there is sure to be a party atmosphere at San Siro on Tuesday night.
A club of Inter's size should be regulars on the biggest stage in club football, but the 2018-19 campaign will be their first in the Champions League since 2011-12, having qualified 10 years in a row prior to that.
The Nerazzurri will be eager to focus on the future rather than that fallow period, although they have been handed a difficult assignment on their return to the big time with Spurs, Barcelona and PSV alongside them in Group B.
Inter have not exactly provided much cause for optimism during the opening stages of the Serie A season either, amassing four points from their first four games, including a home defeat at the hands of newly-promoted Parma on Saturday.
Indeed, Inter are now winless in their last four home matches across all competitions - a poor run which includes three defeats and stretches back more than five months.
Consequently, pressure continues to mount on the shoulders of Luciano Spalletti, around whom questions have lingered since last season despite him steering Inter back into the Champions League courtesy of a fourth-place finish in Serie A.
The Inter hierarchy handed the Italian a new contract just last month, though, so they clearly have belief that he is the man to restore them to their former glories, both domestically and on the European stage.
It is worth remembering that Inter are the last Italian team to have won this trophy - doing so as part of their treble season under Jose Mourinho in 2010 - but that will feel like a long time ago now and last season they were without any sort of European football for the third time in the space of five years.
Not since 2014-15 have they made it past the group stages of a European competition, although they have progressed from their last eight Champions League groups, last being eliminated at this stage of this competition in 2003-04.
The odds are against them continuing that run this season, but Spalletti will be hoping that the long-awaited return of Champions League football could be enough to kickstart their campaign.
Recent form (all competitions): LDWL
A trip to San Siro will evoke mixed memories for Tottenham fans, who visited the stadium in their debut season in this competition in 2010-11 and saw Gareth Bale put in one of the all-time great individual performances with a hat-trick - albeit in a 4-3 defeat.
Fast forward to 2018-19 and while this Spurs team are far less reliant on one man, their recent dip in form has coincided with questions over the fitness of star striker Harry Kane.
Kane continues to insist that he is not suffering from fatigue, but the clamour for him to be rested sooner rather than later is just the latest in a long line of off-field issues manager Mauricio Pochettino has had to contend with this season.
From the delayed move to a new stadium to the lack of summer transfer business and having nine players return late after reaching the final week of the World Cup to his captain being charged with drink-driving, it has been far from plain sailing for Tottenham so far.
The troubles have begun to show on the pitch too, with Spurs coming into this match off the back of successive Premier League defeats for the first time since May 2016 - most recently going down 2-1 at home to Liverpool on Saturday.
In truth that defeat could have been a lot worse for Spurs, who almost salvaged something from a game they should have been out of within the opening 45 minutes, but it still leaves them facing the prospect of three successive losses in all competitions for the first time since March 2014.
However, unlike on their last visit to face Inter eight years ago it is Spurs who have the greater Champions League experience in recent years, with this their third consecutive season in the group stages of the competition.
Pochettino's side can take great confidence from last season's performances too, when they topped the group ahead of eventual champions Real Madrid and Borussia Dortmund before crashing out at the hands of Inter's domestic rivals Juventus.
Spurs were unbeaten on the road during last season's competition despite visiting the Bernabeu, Westfalenstadion and the Allianz Stadium, and they have already cruised past Manchester United at Old Trafford this season too.
That victory was hailed as a statement of intent from Pochettino's men, but it could take a similar result at San Siro to restore that feeling following their back-to-back defeats either side of the international break.
Recent form (all competitions): WWWLL
Dele Alli is facing a late fitness test to determine whether he is ready to return from a hamstring injury for this match, although he is expected to once again miss out.
Michel Vorm will continue to deputise in goal for Lloris despite being criticised for his role in both Liverpool goals at the weekend, and Pochettino is expected to revert to a back three having switched his tactics for that match.
Wembley goalscorer Erik Lamela is pushing for a start alongside Son Heung-min, Ben Davies and Serge Aurier as Pochettino considers rotating his squad to keep them fresh ahead of a packed spell of fixtures.
Inter rested Mauro Icardi at the weekend following a recent muscle injury and will almost certainly welcome the skipper back into their side, but Sime Vrsaljko is likely to miss out with the knee injury he sustained on international duty.
Inter possible starting lineup:
Handanovic; D'Ambrosio, De Vrij, Skriniar, Dalbert; Brozovic, Gagliardini; Perisic, Nainggolan, Candreva; Icardi
Spurs possible starting lineup:
Vorm; Alderweireld, Sanchez, Vertonghen; Trippier, Dier, Dembele, Davies; Eriksen; Kane, Son
Head To Head
The most memorable previous meeting between these two sides saw Bale score a hat-trick and still end up on the losing side at San Siro in 2010-11, with Inter running out 4-3 winners before Spurs got revenge with a 3-1 triumph in the return fixture at White Hart Lane.
These two sides also faced off in the 2012-13 Europa League last 16, and once again there were goals galore with Spurs winning 3-0 at home before losing by the same scoreline in Italy, forcing extra time which Tottenham eventually won on away goals despite a 4-1 defeat on the night.
Inter have won 10 and lost just two of their 15 home games against Premier League opposition - including winning each of their last four - whereas Spurs have only won one of their previous eight visits to Italy, although that did come at San Siro against AC Milan in 2010-11.
We say: Inter Milan 1-2 Tottenham
Inter have not been impressive so far this season and, while Spurs have also been below par in their last two outings, they have the quality to come away with a famous victory on Tuesday night. Pochettino will be demanding a response from his players, and they often rose to the occasion in this competition last season.