The Reds take on the Spanish side over two legs, with the second to be played at Anfield.
Among the dangermen will be former international striker Roberto Soldado, who joined Villarreal last summer after two poor seasons in the Premier League.
Yet Soldado will not have fond memories of playing at Anfield. This is how his one and only appearance with Spurs ended...
He was stretchered off after landing badly going up for a challenge with an apparent hamstring injury, minutes after Liverpool defender Jon Flanagan had scythed him down with a crunching tackle.
Tottenham lost the game 4-0, with then boss Tim Sherwood's side devoured by an electric performance from a Luis Suarez inspired Liverpool.
The following season Soldado was an unused substitute at the stadium as Spurs slipped to a 3-2 loss to Liverpool, another miserable night for the Spaniard.
He has been a regular for Villarreal this season despite being inconsistent in terms of goalscoring, netting eight goals in 38 appearances in all competitions.
The 30-year-old will be hoping to add to this tally, and to enjoy better success than last time on his next visit to Anfield.