The Italians host the Basque outfit at the San Paolo stadium hoping to take an advantage heading into the return leg in Spain on 27 August. Napoli, who finished third in Serie A last season and lifted the Coppa Italia, are considered favourites to reach to the group stages for the third time but Benitez has warned his players to expect a difficult tie against Los Leones.
"We will face a great team and the second leg will be in an incredible (San Mames) stadium," Benitez said to Spanish newspaper Marca. "The (San Mames) crowd is like their 12th man. Athletic's strongest weapon is the group, with players who have been together for many years and have the support of a city that never loses its passion.
"I respect Athletic Bilbao a great deal, but I trust my Napoli. We have players who came in late from World Cup duty, like (Argentinian striker) Gonzalo Higuain, and new players that have yet to adapt to the team but I've seen positive signs."
Benitez is confident his side can join Italian giants Juventus and Roma in the group stages of the Champions League. "My team arrives ready for this tie," the Spaniard said. "We have the right mentality and we too can count on great passion."
Last season, Napoli became the first team since 1997 to be eliminated from Europe's elite club competition in the group stages with 12 points in Benitez's first year in charge. Athletic finished fourth in the Spanish La Liga in the 2013/14 campaign.
Meanwhile, over in Turkey, Arsenal will attempt to reach the group stages for the 17th consecutive season as they go up against Slaven Bilic's Besiktas. Since reaching the final in 2002 Bayer Leverkusen have struggled to reach the later rounds of the Champions League. They can start well this time round by overcoming FC Copenhagen, their first-leg hosts in Denmark.
Red Bull Salzburg hotshot Jonathan Soriano will be eager to show what he can do at a higher level after taking the Europa League by storm last season but Swedish champions Malmo are standing in his way. Romania's Steaua Bucharest won the continent's greatest club prize in 1986 and now host Ludogorets of Bulgaria.
On Wednesday night Celtic will look to make the most of their European reprieve by getting the better of Slovenian champions Maribor at Ljudski vrt. The Hoops were beaten 6-1 by Legia Warsaw in the third round of qualifying but, after the Polish club were found to have fielded an ineligible player towards the end of the second-leg match, Celtic were handed a 3-0 walkover win.
Legia's appeal to UEFA failed and they will take part in the Europa League play-off round unless an appeal to the Court of Arbitration for Sport is successful. Celtic must now do the business on the pitch in Maribor to prove they deserve their second chance.
The showdown at Stade Pierre-Mauroy looks to be a mouthwatering prospect as Ligue 1 outfit Lille entertain Porto. Both recent domestic champions finished third in their respective leagues last season and the Portuguese club are especially keen to make amends by enjoying success in the competition they won only ten years ago.
Their former head coach, Andre Villas-Boas, is hoping to taste Champions League football once again as he takes Zenit St Petersburg to Standard Liege, who were European Cup semi-finalists back in 1962. Elsewhere, Slovakian champions Slovan Bratislava welcome their Belarusian counterparts BATE Borisov and Danish Superliga winners AaB play host to Cypriot First Division title holders APOEL FC.