Napoli nearly took the lead inside the opening quarter of an hour after a low Gonzalo Higuain strike was spilled by Federico Marchetti before the Lazio keeper retrieved the ball ahead of Marek Hamsik.
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Gli Azzurri squandered another opportunity midway through the first half as David Lopez's poor effort from the edge of the area flew well wide of Marchetti's goal.
On the stroke of half time, Lazio looked to have put a Champions League berth beyond the hosts when an incisive through-ball from Senad Lulic found Antonio Candreva in space before the Italy international tucked his shot low beyond Andujar.
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However, it was star striker Higuain who pulled a goal back on 55 minutes after Callejon timed his pass across the six-yard box to perfection, giving the Argentine international the easy task of slotting into an empty net from close range.
Napoli continued to pour forward and a few moments later, almost found an equaliser through Mertens before Stefan de Vrij cleared off the line to keep Lazio ahead.
Callejon then forced another save out of Marchetti as Le Aquile struggled to hold on to their lead before the home side's task was briefly made easier when Parolo was dismissed for a second bookable offence.
The hosts then got back on level terms thanks to Kalidou Koulibaly's persistence, which saw him dispossess Felipe Anderson on the left flank before Mertens teed up Higuain, who coolly slotted home to the delight of a very vocal home crowd inside the Stadio San Paolo.
Napoli's hopes suffered a setback when Faouzi Ghoulam was sent off for a poor challenge, which earned him a second yellow card in four minutes.
They were then awarded a penalty for Lulic's sliding tackle on Christian Maggio, giving Higuain the chance to complete a crucial hat-trick.
However, the Argentine forward's spot kick was a poor one as it drifted harmlessly over Marchetti's crossbar.
His penalty miss was punished when Onazi, who had only come on as a substitute 99 seconds earlier, latched on to to Candreva's pass late on before tucking the ball past Andujar with his first touch of the game.
Lazio made sure of victory in stoppage time when another substitute, Klose, slotted home as the visitors sealed third place in Benitez's final match in charge of Napoli.