The Reds can also win their group with a victory, with Sevilla facing strugglers NK Maribor in the group's other game - meaning a draw would likely see them end up in second.
Liverpool wasted a chance to qualify with a game to spare last time out, surrendering a 3-0 half-time lead away at second-placed Sevilla to set up an anxious meeting with the Russian champions at Anfield.
Spartak can qualify with a win with the groups decided on head-to-head records rather than goal difference, meaning victory by any score-line would put them into the next round and likely condemn Liverpool to the Europa League.
Anything less than three points however means that the visitors will be the team to drop into Europe's second-tier competition.
While the difference between finishing first and second is minimal this year, with Real Madrid, Bayern Munich and Juventus all potential opponents even if Jürgen Klopp's side win Group E, it would surely act as a psychological boost at the least.
Given the excellent performance of the other English teams involved, were Liverpool to finish second behind Sevilla then they would face one of Paris Saint-Germain, Barcelona, AS Roma or Besiktas - with the latter the only real favourable draw having last reached this stage of the Champions League in 1992-93.
Though Liverpool also have a high-stakes Merseyside Derby contest with Everton to think about on Sunday, Champions League knockout stage qualification is a vital objective for their season having fought so hard to finish in the top four last term.
And they will be confident of securing just that having gone eight matches unbeaten in all competitions, winning six and scoring at least three goals in seven of those games.
They thrashed Brighton & Hove Albion 5-1 in their previous outing even despite their recent rotation, with Sadio Mané an unused substitute and due to absences, Emre Can and Georginio Wijnaldum making up a make-shift back-three.
But Massimo Carrera's Spartak too are also on good form, winning four of their last five and like Liverpool sitting fourth in their domestic division.
Liverpool and Spartak drew 1-1 in Russia with the Merseyside outfit the far superior side, though the People's Team were without several key players including talisman Quincy Promes - who has hit double figures in all of his four seasons in Russia, with 11 goals so far this term.
But an early goal for the visitors could provoke a nervy atmosphere on L4 with Spartak looking to produce a shock result.
Anything but progression to the next round would be sure to spell widespread criticism and ridicule towards Liverpool, who are well capable of reaching the latter stages of this tournament given the potency of their front-line.
Joël Matip will play no part for Liverpool with a thigh injury, although his problem is not as serious as first feared - with suggestions he could be ruled out until the New Year.
Joe Gomez, who missed their win over Brighton at the weekend with a virus, and Ragnar Klavan, who made the bench after missing the 3-0 win at Stoke City last Wednesday with his own bout of illness, are both available again.
Alberto Moreno is likely to return at left-back after summer signing Andrew Robertson replaced him on Saturday for his first appearance since September 16th.
Likewise Mané should start after being rested at Brighton with Roberto Firmino, Mo Salah and Philippe Coutinho all expected to join him.
Adam Lallana will not be involved as he continues to build towards full fitness after sustaining a few niggles following his long-term thigh injury.
Left-back Dmitri Kombarov is unlikely to feature after breaking a rib in a 3-1 win over Zenit St Petersburg last Monday, while long-term absentees Artem Timofeev and Jano Ananidze are out.
Georgi Tigiev, unavailable since September, remains sidelined for the trip to England.
Recent form (all competitions)
Spartak Moscow: WWDWW
Brighton & Hove Albion 1-5 Liverpool (Can, Firmino x2, Coutinho, Dunk OG)
Arsenal Tula 0-1 Spartak Moscow (Glushakov)
Liverpool are unbeaten against Spartak Moscow in the Champions League - winning twice and drawing once, their previous meeting this season. Their only meeting at Anfield came in October 2002, when Liverpool won 5-0.
The Reds are unbeaten in their last seven Champions League games - although five of those have ended with draws.
Spartak Moscow have only lost one of their last 12 matches in all competitions since a 1-1 draw with Liverpool in September, their only defeat coming away at Sevilla (2-1). They beat the Spanish side 5-1 on home soil.
Spartak have only win six of their last 40 Champions League games, drawing eight and losing 26.
The Russians have also lost four of their last five Champions League away games - drawing at Maribor in the only match they did not lose.
Spartak have only kept one clean sheet in their last 15 games in this competition.
Three of Liverpool's last four goals in this tournament have come from corner-kicks.
Spartak have only reached the knockout stages once from their last 11 campaigns in the Champions League, in 1995-96.
In seven European appearances this season, including Liverpool's two-legged qualifier with Hoffenheim, Firmino has scored six goals and recorded three assists.
Should the Brazilian forward score on Wednesday night, he would equal his best-ever goal tally for Liverpool (11).
Of the last 31 teams since 2003-04, 28 have gone on to reach the Champions League knockout phase after claiming eight points from their first four group games, as Liverpool did.