Marek Hamsik snatched an lead early in the second half but the Basque side roared back to seal their place in the Champions League group stages
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 further gloss on the scoreline but will nonetheless take their 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.
Higuain was then sent through only to be denied by a close offside call, before Aritz Aduriz brought a smart stop out of Rafael - 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 Rafael 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 who 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 visitors began to look the more relaxed and controlled side - but their lead did not last long. On 61 minutes, Aduriz was picked out unmarked by Susaeta from a corner, and he fired low past Rafael to restore parity.
Higuain then tested Iraizoz with a run and shot, but just eight minutes later, Athletic were ahead. Rafael 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 they pushed for an equaliser, 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.