Hapoel beat Inter Milan twice and drew twice with Southampton, beating them on away goals, in the Europa League Group Stage, to qualify for the knockout round.
However, Hapoel lost twice to Slavia Prague, leaving them in second place in Group G and in the unseeded half of the draw today.
Hapoel manager Barak Bakhar said: "It's an interesting draw against a very tough team.
"It will be a challenge but we will find out about them and come prepared for the matches in the best possible way.
"I think we have already proven that we need fear nobody in Europe."
The Israeli champions will host Besiktas on February 16 and travel to Istanbul for the second leg on February 23.
The match in Istanbul will raise serious security concerns after a suicide bomber killed 38 people outside of Besiktas' Vodafone stadium over the weekend.
Israel's Foreign Ministry issued a warning to Israelis not to travel to Turkey in April due to increased terrorism there.