Benitez's men host Athletic at the Stadio San Paolo in the first leg of an enticing meeting that arguably represents the pick of the play-off round clashes.
Napoli head into the tie as favourites, but are sure to face a tough task against a team that finished fourth in La Liga last term.
The Serie A club were unfortunate to be eliminated in the Champions League group stages last season, but Benitez claims it would not be disastrous if they were to be knocked out by Athletic.
"If Napoli don't make it? It has been said it would be a tragedy, but Napoli has played few times in the Champions League," said the Spaniard.
"Many strong clubs are not in it at all, as we have seen with Manchester United, but we know that it is important from both the sporting and economic points of view, but we should not be in fear.
"The preliminary round is crucial from an economic and image point of view, but that does not mean that we cannot grow the same without the Champions League.
"In any case there is the Scudetto, the Coppa Italia and Europa League. My experience is in playing to the end, not in thinking about what happens if I lose.
"Athletic says they have nothing to lose, yet for us it will be a tragedy. I do not hide the fact that it is essential, but it is not the end of the club."
Benitez is expecting a fiercely competitive clash given Athletic's style of play.
"Athletic know how to do everything - pressing, counter-attacking, possession," he added.
"They have known each other for many years. [Winger Iker] Muniain says that they do not know how to speculate with their play, that they always play their game, and I believe that too.
"They can defend, but they also pressure high up the pitch, they do many things. Tactically it will be interesting and will be played with great intensity."
