Rafa Benitez could not get his side past Athletic and into the group stage of the Champions League.
Aritz Aduriz scored twice before Ibai Gomez added a third in a blistering 15-minute spell in the second half after Marek Hamsik had put Napoli ahead.
The home side spurned a number of other opportunities to put gloss on the score line but will nonetheless take its place in the group-stage draw on Thursday, while Rafa Benitez is left to ponder life in the Europa League.
In what was a relatively cagey opening, Athletic started the strongest, pressing high up the pitch and forcing Napoli to concede possession quickly.
It was Napoli with the first half chance, however, as Jose Callejon latched on to Marek Hamsik's cut back only to lash a half volley over the bar from 20 yards.
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Higuain was then sent through only to be denied by a close offside call, before Aritz Aduriz brought a smart stop out of Raffael - though again he was narrowly offside.
Higuain then flashed a half volley narrowly wide of the near post before Gurpegi spurned a glorious opening, heading past the near post as he arrived unchallenged to meet Benat's corner.
Athletic continued to press, with De Marcos forcing a nervy parry from Raffael before the resulting corner found its way to Iker Muniain, who picked out Aymeric Laporte unmarked at the far post only for the youngster to fire well over the bar.
However, it was Napoli which struck first just after break. Balenziaga headed a chipped long ball straight to the feet of Hamsik, who took a touch and buried it in the bottom corner.
Callejon was then sent racing clear only for Iraizoz to hurtle off his line to deny him as the visiting side began to look the more relaxed and controlled side - but the lead did not last long. On 61 minutes, Aduriz was picked out unmarked by Susaeta from a corner, and he fired low past Raffael to restore parity.
Higuain then tested Iraizoz with a run and shot, but just eight minutes later, Athletic was ahead. Raffael raced off his line to clear a long ball from Laporte and got in a mess with Raul Albiol, allowing Aduriz to stroll through and stroke the ball into the unguarded net.
Benitez threw on Duvan Zapata and Lorenzo Insigne as the Italian side pushed for an equalizer, but on 74 minutes, the home side made the game safe. Some brilliant build-up between Iker Muniain and Unai Lopez allowed the latter to chip the ball through to Aduriz, who left the ball for the onrushing Ibai to fire into the bottom corner.
Napoli pressed again but Aduriz should have made it 4-1 when he scooped Muniain's cross over the bar from point-blank range, but ultimately the Basque side saw out the final few minutes with minimal fuss to land a place in the group-stage draw on Thursday.