Spartak held the Gers to a goalless draw at Ibrox last month but the latest encounter is expected to be a different affair.
Here are the talking points ahead of the Otkritie Arena clash.
Goal threat hampered
Rangers have lost attacking midfielder Ryan Kent to a hamstring injury on top of the absence of Kyle Lafferty, who has a thigh problem. Teenager striker Dapo Mebude was drafted into the travelling party and Steven Gerrard will hope there are no further blows to his forward players during the game.
Win or bust for Spartak
Rangers sit top of the group on five points after three matches, three ahead of bottom side Spartak. Home boss Raul Riancho admits they will have to be far more attacking than they were when they contained the Light Blues at Ibrox, which could help open things up on the break for Gerrard's men.
Caretaker boss Riancho accused some fans of wanting to destroy their own club after they showed their anger at the way it is being run – and results on the park – following a fourth consecutive home defeat in the league on Sunday. A good start for Rangers could get the crowd on the home side's backs again, while the 45,000-capacity stadium is tipped to be less than half full.
A double win for Rangers and Villarreal would put the Light Blues five points clear of Rapid Vienna, who host the Spanish team, and put Gerrard's men in touching distance of the knockout stages.