The Reds make the 4,000-mile-round trip to the Russian capital having drawn at home to La Liga side Sevilla in their opening European game at Anfield earlier this month.
Reigning Russian Premier League champions Spartak meanwhile opened their continental campaign with a 1-1 draw away at Slovenian outfit NK Maribor.
Liverpool's performances in the Champions League so far, beating TSG 1899 Hoffenheim 6-3 in the final qualifying round in addition to their draw with Sevilla, have encompassed their transparent strengths and weaknesses.
Jürgen Klopp's side, as shown in their indifferent Premier League form, have shown the tendency to self-destruct defensively despite the quality of their attack.
That has cost them in a number of games, though the stellar display of Philippe Coutinho helped them beat Leicester City 3-2 in a pulsating encounter on Saturday evening to end a four-game streak without a win in all competitions.
Their unreliable back-line leaves them constantly vulnerable, as shown in their draw against Sevilla, a game which the Spanish side might have won late on despite Liverpool having controlled and created more opportunities throughout.
Massimo Carrera's Spartak side, meanwhile, sit in a disappointing 7th place in the league after winning just three of their first 11 games of the domestic season.
They only earned a draw at home to bottom-of-the-league Anzhi Machachkala thanks to a 92nd-minute equaliser at the Otkrytiye Arena and they remain 13 points behind leaders Zenit St Petersburg.
A trip to Russia would generally be considered a tricky tie, with Spartak having won five of their eight home games against English opposition. But The People's Team have lost their last three European home matches, and four of the last five.
They have not won a European fixture at all since October 2012, eight games ago, and so both teams go looking to end their own respective unfavourable winless streaks in continental competition.
Yet the away side will be wary not to underestimate Spartak
With Sevilla expected to beat Maribor at home, Liverpool will hope to win in Russia to keep pace with the Spanish side as they look to seal top spot and reach the next stage of this competition for the first time since 2008-09.
Liverpool will be without right-back Joe Gomez after he picked up two yellow cards against Sevilla and a one-match ban. Trent Alexander-Arnold will start in his place.
The visitors welcome back Sadio Mané from a three-game domestic suspension, the Senegalese winger likely to join Roberto Firmino and Mohamed Salah in the front-three.
Playmaker Philippe Coutinho, who started on the left at Leicester, could drop into midfield with Jürgen Klopp enjoying a plethora of options to pick from for his midfield trio. Emre Can and captain Jordan Henderson are the most likely two to partner Coutinho in the middle.
Loris Karius will start in goal having been selected over usual first-choice Simon Mignolet as the club's starting goalkeeper for Champions League matches.
Nathaniel Clyne (back) and Adam Lallana (thigh) remain Liverpool's only injured players, while Marko Grujić and Ben Woodburn remain the only notable absentees from their 21-man travelling squad.
Spartak winger and talisman Quincy Promes - previously a Liverpool transfer target - is a doubt.
The Netherlands international is the club's top goalscorer this term but missed Saturday's draw with Anzhi due to a calf injury.
Towering striker Zé Luís and captain Denis Glushakov were also absent at the weekend. Georgi Tigiev, Roman Zobnin and Artem Timofeev are long-term absentees all with cruciate problems.
Recent form (all competitions):
Leicester City 2-3 Liverpool (Salah 15, Coutinho 23, Henderson 68)
Spartak Moscow 2-2 Anzhi Machachkala (Luiz Adriano 14, Melgarejo 90)
Liverpool have failed to win any of their last six Champions League group games, their longest run without victory in the competition. Their last win was in September 2014 at home to Ludogorets Razgrad.
Liverpool have won only one of their previous seven Champions League away games (D3, L3). That came in November 2009 against Hungarian side Debreceni VSC.
Spartak Moscow and Liverpool's only previous Champions League encounter was in the 2002-03 first group stage, where Liverpool won 3-1 in Moscow and 5-0 at home.
In total they have met four times, both teams winning two games. Spartak won 6-2 on aggregate in a 1992 two-legged UEFA Cup Winners' Cup clash.
Spartak have only won two of their previous 17 home games in this competition, losing 10, and have won just five of their last 36 games - home or away - losing 25.
The Russian outfit have only managed to keep one clean sheet in their last 18 home games in the Champions League and have not kept a shut-out in any of their last 11 outings.
All of Spartak Moscow's last 19 goals in this competition have been scored from inside the box.
Spartak's best ever Champions League campaign saw them reach the semi-finals in 1990–91. They have reached the knockout rounds just twice in their last 11 appearances, last in 2000-01.
The Russian club's overall record against English opposition reads: W9 D2 L6. At home, it is: W5 D1 L2.
Only Anzhi (25), who held Spartak to a draw on Saturday, have conceded more goals in the Russian Premier League than Spartak (17) this season.
The top Champions League goalscorers in Liverpool's current squad - excluding qualifiers - are Salah and Alex Oxlade-Chamberlain, both with just four career goals in the tournament.