Andre Schürrle cancelled out Ola John's great individual opener for the home side, but Nemanja struck what would prove the winner on the night soon after for the hosts during a frantic second-half phase.
Benfica saved by the post
Bayer started brightly, Andre Schürrle forcing home keeper Artur Moraes into action with a half-volley a couple of minutes in. With twelve minutes played, the Bundesliga's third-placed club came altogether closer to going in front when Stefan Kießling freed up Daniel Carvajal down the right and latched onto the Spanish full back's pinpoint return with a shot that clattered the post.
Four minutes later, Benfica carved out their first chance of note as Nicolas Gaitan outjumped Carvajal to pull a fine reflex save out of Bernd Leno. As the half unfolded, the hosts gradually warmed to the task and Leverkusen had a let-off half an hour in when Ola John, freed up from the midway line by Almeida, failed to bring the ball properly under control.
Further chances go begging
It was by no means one-way traffic in the Estadio da Luz however and only some swift legwork from Artur prevented Schürrle squeezing a shot past him seven minutes before the interval. Two minutes on from that, Bayer's livewire Germany international cut in from the left and drilled in a near-post effort that rebounded off the woodwork once again to the home side's advantage.
No goals at the midway point, but five minutes into the second half Leverkusen looked to have made the breakthrough against the Portuguese record champions as Kießling tucked home Carvajal's square ball in. The celebrations were brief however as the on-form frontman was adjudged to have been narrowly offside.
Ten minutes later, the ball was in the net at the other end of the pitch - and there was no doubt about this one. John cut in from the flank leaving Castro and Carvajal in his wake before curling a superb finish past Leno into the top corner. Two goals were Bayer's target now and they almost got the first of them in the 68th minute, when only a superb reflex save from Artur prevented Simon Rolfes hauling the Werkself level on the night.
With quarter of an hour to go though, they managed just that. Seconds after Benfica sub Eduardo Salvio had sent a free header wide, Arkadiusz Milik - fresh on the field himself for Bayer - teed up a rebound just inside the hosts' box for Schürrle, who volleyed home with aplomb. The tie was balanced on a knife-edge again but, unfortunately for Leverkusen, only for a couple of minutes. The Bundesliga outfit failed to clear their lines decisively following a corner and Lima had time aplenty to pick out Matic, who supplied the headed finish at the far post.
Lima and Salvio were altogether less clinical given the chance to finish things off at the end of a swift counter-attack not long after that and Gaitan was likewise unable to force the fall past Leno in the final minute of regulation time, but it mattered not come the final whistle.
Benfica: Artur - Almeida, Luisao, Garay, Melgarejo - Martins, (Salvio 53'), Matic, Gaitan - Perez, Cardoso (Lima 64'), John
Leverkusen: Leno- Carvajal, Wollscheid, Toprak, Boenisch - Reinartz (Milik 74') - Bender (Hegeler 57'), Rolfes - Castro, Schürrle - Kießling
Goals: 1-0 John (60'), 1-1 Schürrle (75'), 2-1 Matic (77')