Beleaguered European giant Barca crashed out of the Champions League group stages following a 3-0 loss to Bayern Munich.
It is the first time since 2003-04 that the Camp Nou club will not appear in the knockout stages of Europe's premier club competition.
Instead, the Europa League offers Xavi's side some hope of continental redemption, although Napoli – fourth in Serie A – represent tough opponents for a side languishing eighth in LaLiga.
Sevilla, six-time winners, will take on Dinamo Zagreb, while Scottish champions Rangers were handed a stern test after being drawn to meet Borrusia Dortmund.
Elsewhere, Porto and Lazio go head-to-head, while Atalanta face Olympiacos, with all ties being decided over two legs.
Europa League knockout round play-off draw in full:
Sevilla v Dinamo Zagreb
Atalanta v Olympiacos
RB Leipzig v Real Sociedad
Barcelona v Napoli
Zenit v Real Betis
Borussia Dortmund v Rangers
Sheriff Tiraspol v Braga
Porto v Lazio