Leverkusen's most recent defeat by a Spanish team came at the hands of Villarreal in last season's Europa League round of 16. They had also drawn twice with Atletico Madrid earlier in the same competition.
The last time the German team beat an outfit from Spain was in 2004 when they defeated Real Madrid in the group stages.
Michael Ballack, who featured in the 2002 Champions League Final defeat by Real, said the Germans had the potential to go a long way again this season.
"Last year we showed what we are capable of by finishing second in the Bundesliga - why shouldn't the current team succeed as well?" said the Leverkusen midfielder.
The former Chelsea player acknowledged, however, that Valencia had more international experience.
"In recent years they have always played in the Champions League," said Ballack. "They are simply much more steady and more stable than Leverkusen but our goal is to reach second spot in the group."
Chelsea, on four points from two games, are expected to finish top in a section that also includes Racing Genk of Belgium.
Leverkusen have three points, Valencia are on two while Genk have one point.
"We are playing at home so the three points are obligatory and if we then draw at Valencia that would be perfect," said Leverkusen defender Gonzalo Castro.
The home team, eighth in the Bundesliga, are without Brazilian midfielder Renato Augusto (knee surgery) but Omer Toprak is expected to be back in defence.
Valencia, knocked out in the last 16 by Schalke 04 last season, are fifth in La Liga.
They conceded a stoppage-time penalty in a 1-1 draw at Real Mallorca on Saturday and coach Unai Emery was unhappy with his side's inability to convert possession into goals.
Valencia defender Adil Rami said they would be aiming to take maximum points on Wednesday.
"We are going there to win. It's a very important game for us," he said.
"We are in a slightly difficult situation but we have a lot of quality on the goal-scoring front."
Bayer Leverkusen: 23-Bernd Leno; 14-Hanno Balitsch, 3-Stefan Reinartz, 21-Omer Toprak, 24-Michal Kadlec; 6-Simon Rolfes, 8-Lars Bender, 27-Gonzalo Castro, 18-Sidney Sam, 9-Andre Schuerrle; 11-Stefan Kiessling;
Valencia: 1-Diego Alves; 23-Miguel, 4-Adil Rami, 18-Victor Ruiz, 17-Jordi Alba; 6-David Albelda, 19-Pablo Hernandez, 10-Ever Banega, 16-Sergio Canales, 22-Jeremy Mathieu; 9-Roberto Soldado.
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