Missing a number of key players, Maurizio Sarri saw his side fall to a 3-1 home defeat in the first leg last week.
However, Die Roten Bullen have just lost twice in 15 home matches this season, and bet365 make them 8/11 (1.73) favourites to come out on top once again.
Just one of the guests' last 16 fixtures has resulted in a draw, but you can get odds of 14/5 (3.80) on them playing out a stalemate in this one.
Ralph Hasenhuttl will be without the ineligible Ademola Lookman and long-term injury absentee Marcel Halstenberg, although Stefan Ilsanker is available after missing the first leg through suspension.
Dries Mertens will return from suspension for the Partenopei, who are still missing Arkadiusz Milik, Faouzi Ghoulam and Vlad Chiriches through injury.
Leipzig worthy favourites
Although regarded by many as front-runners to lift the trophy when the draw for the last 32 was made, Sarri's team do not seem particularly invested in European competition this campaign.
With their focus centred on maintaining their position at the top of Serie A as they target a first Scudetto since 1990, the Italians dropped unceremoniously out of the Champions League at the first hurdle.
Preview and predictions
Having rested some key players in their defeat at the Stadio San Paolo, it is hard to see them putting out a particularly strong team for this trip with the tie all but wrapped up.
Instead, those 8/11 (1.73) odds seem generous on RB Leipzig enjoying another victory against a Napoli team that lost all three of their away games in the Champions League group stages.