Simone Inzaghi's side have nine points so far, one behind already-qualified Borussia Dortmund and two above Brugge, with whom they drew 1-1 in the reverse fixture. Another draw would therefore be enough for Lazio to make the knockout rounds; Brugge simply must win to go through.
With the fourth side in the section, Zenit, trailing behind on one point, both Lazio and their Belgian visitors are guaranteed to finish no lower than third and so claim the consolation of a Europa League slot.
Nonetheless, nothing but qualification will do for Inzaghi, as his team seek to emulate - or even surpass - the club's most successful Champions League campaign in 1999-2000, when they reached the quarter-finals before losing to eventual runners-up Valencia.
Lazio can, in fact, still top the group if they win and Dortmund do not take all three points at Zenit, or if they draw and Lucian Favre's men lose in Russia.
Their opponents this week proved more than a match for the Aquile back in October, with both goals in Belgium coming in the first half - Joaquin Correa giving the visitors an early lead before Brugge midfielder Hans Vanaken levelled from the penalty spot just ahead of the half-time whistle.
That result was Lazio's first draw in 19 European games but they have drawn three of their five Group F fixtures 1-1 - all away from home - in Brugge, St Petersburg and, last time out, Dortmund.
Intriguingly, they have also won both home matches in this campaign 3-1, but Brugge will be buoyed by the fact that the Biancocelesti have not kept a clean sheet in any of their 16 most recent Champions League group games - including their last eight at home.
At the weekend, Sergej Milinkovic-Savic - slowly retuning to somewhere near his peak after a spell in self-isolation - created a goal for last season's capocannoniere Ciro Immobile before curling in a delightful free kick, but Lazio were made to graft for a 2-1 win at Serie A surprise side Spezia.
The Ligurian outfit hit the woodwork twice from their 15 goal attempts and enjoyed two-thirds of possession against their supposed superiors, which may concern Inzaghi in light of a packed itinerary and an already-stretched squad.
Meanwhile, Tuesday's opponents Brugge beat lowly Sint-Truiden 1-0 to stay top of the Belgian Pro League ahead of the trip to Rome - a must-win encounter for Philippe Clement's side.
After kicking off Group F with a 2-1 win at Zenit, the Blauw-Zwart took only one point from their two subsequent home games against Lazio and Dortmund, but a 3-0 home win against Zenit last time out has kept them in contention.
That win at Jan Breydel Stadium was one of only three victories for Brugge in their last 23 fixtures in the Champions League proper and the first of those wins to come at home, ending a run of 12 home matches in the group stage without victory.
In their eighth Champions League group appearance overall, the side now managed by former Coventry City midfielder Clement have never progressed to the knockout rounds but are within touching distance of that goal this time.
Former PSV man Vanaken and teenage starlet Charles De Ketelaere have provided the chief Brugge goal threat so far, with reports of interest from AC Milan and Napoli coming as no surprise to regular observers of 19-year-old attacking midfielder De Ketelaere.
Both will need to demonstrate the full extent of their talents in the Italian capital, as though their continental record could be best described as patchy, Lazio have now won their last three home European matches, and seven of the last 10.
However, Brugge have lost only two of their last seven away games in the group stage and will not easily roll over in the battle to reach the promised land of Europe's elite 16.
Lazio Champions League form: DWDDW
Lazio form (all competitions): DWWLDW
Club Brugge Champions League form: WLLDW
Club Brugge form (all competitions): WWLDWW
The controversial COVID-19 testing confusion around Lazio seems to have cleared and all of the players affected have returned to action, including goalkeeper Thomas Strakosha, who was back on the bench at the weekend but is not assured of a start - experienced stopper Pepe Reina has proved an able deputy.
Coach Simone Inzaghi will pick two from three centre-backs - Luiz Felipe, Wesley Hoedt and Stefan Radu - to complete the back three alongside Francesco Acerbi, who made some uncharacteristic errors on Saturday but is generally their defensive standard bearer.
Brugge boss Phillipe Clement has generally utilised a 4-1-3-2 setup in Europe, though has occasionally switched to a lone frontman. He has the luxury of an essentially full squad to select from, with Senegal forward Krepin Diatta and Dutch winger Noa Lang the favourites to start alongside in-form Charles De Ketelaere.
In defence, Brandon Mechele and Odilon Kossounou should form the central defensive pairing ahead of goalkeeping stalwart Simon Mignolet, whose experience at this level - both of highs and lows - could be vital.
Lazio possible starting lineup:
Reina; Felipe, Hoedt, Acerbi; Lazzari, Milinkovic-Savic, Leiva, Alberto, Marusic; Correa, Immobile
Club Brugge possible starting lineup:
Mignolet; Mata, Sobol, Kossounou, Ricca; Vormer, Balanta, Vanaken; Diatta, De Ketelaere, Lang
We say: Lazio 2-1 Club Brugge
Though Lazio will be most observers' favourites to progress - justifiably so, given they only need to avoid defeat - it may not be a straightforward passage into the last-16 for Simone Inzaghi's overworked side.
Brugge have had an awful record in the Champions League in recent times but have demonstrated enough potential this term to suggest they can take it to the wire before falling to glorious failure once again - life in the Europa League awaits.