The Bulgarian outfit stunned Lazio in the last 32, to set up an intriguing last 16 clash against the Spaniards, who won Europe's secondary club competition under its former guise of the UEFA Cup in 2004.
Ludogorets also sprang a surprise in the group stage, beating PSV Eindhoven twice as they finished top of a pool also containing Chornomorets and Dinamo Zagreb by six points.
They won five of their six matches in Group B and possess an impressive home record, having lost just three of their 24 matches at the Ludogorets Arena in all competitions this season.
Stoycho Stoev's side were promoted to the Bulgarian top flight for the first time in 2011 and have won back-to-back titles since, leaving traditional heavyweights CSKA Sofia and Levski Sofia in their wake.
Stoev replaced Ivaylo Petev in charge in July and has overseen a golden run that sees them top of the Bulgarian league and in with a chance of reaching the Europa League quarter-finals.
Slovenian striker Roman Bezjak has starred on the European stage so far this term, netting six goals in seven appearances.
Ludogorets are unbeaten in their last eight matches in all competitions but were held to a goalless draw at Lovech, placed second in the Bulgarian top flight, on Sunday.
Valencia also enter this clash on the back of a draw, with Athletic Bilbao coming from behind to secure a point in a 1-1 La Liga draw on Sunday.
The Spanish club have not won in three games in all competitions but remain eighth in La Liga, seven points off a European place.
After being embarrassed in a 3-0 home defeat to Swansea City in their first pool match, Valencia have gone on a seven-match unbeaten run in Europe and topped Group A by five points.
They reached the semi-finals of the Europa League in 2011-12, where they were beaten by eventual winners Atletico Madrid.
New coach Juan Antonio Pizzi, who replaced Miroslav Djukic in December, oversaw his side's 2-0 aggregate win over Dynamo Kiev in their last 32 tie and will now be looking for them to push on.
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