Carlo Ancelotti's side currently top the group with seven points, with the Austrian champions back in third after recording one win and two defeats in their first three matches.
That win is one of just two that Napoli have recorded in their last seven games - a run that was extended by their 2-1 defeat to Roma on Saturday.
The Partenopei could well have equalised in stoppage time against the capital side but in the end they were undone by a slow start in both halves and conceding too many fouls in and around the area, something that they will have to avoid against a Salzburg side brimming with dead-ball specialists.
Ancelotti's men are likely to adopt a gameplan similar to that of two weeks ago, moving the ball quickly when in possession and looking to play through-balls that enable Mertens, Insigne and Jose Callejon to get in behind.
Should Napoli record a win on Tuesday night they could potentially assure themselves of qualification for the last 16 if other results go their way, and it would also mark the first time in the club's history that they have beaten the same side three times in European competition in a calendar year.
The San Paolo has represented something of a fortress for Napoli in recent Champions League games, with the club winning four of their last five fixtures in the competition there.
Jesse Marsch's Salzburg have been a breath of fresh air in this year's Champions League, with their opening three matches featuring a competition record 20 goals.
The club picked up yet another win in the Austrian Bundesliga at the weekend as their rotated XI beat Mattersburg 3-0 courtesy of a Patson Daka treble.
The intensity with which Marsch's side play means that they will always create chances, score goals and pose problems, but it also ensures that when they press in numbers, they often lose their defensive shape.
While that is not normally an issue in domestic competition, it does pose problems in Europe against better and more technical sides, which is why they have conceded nine goals in their opening three games.
Napoli recent form: WDW
Napoli recent form (all competitions): DWWDDL
Red Bull Salzburg recent form: WLL
Red Bull Salzburg recent form (all competitions): WDLWWW
The main selection dilemma for Ancelotti will be whether to stick with Arkadiusz Milik, who has scored in his last three games, as Mertens' strike partner, or to bring back Mexican dynamo Hirving Lozano.
Likewise, the Napoli boss will need to decide whether to stick with the fit-again Manolas or to start Nikola Maksimovic in defence.
For Salzburg, they have a mostly clean bill of health and their ability to rotate domestically means that their major stars are all fit for the trip to Italy.
Napoli possible starting lineup:
Meret; Di Lorenzo, Manolas, Koulibaly, Rui; Callejon, Ruiz, Zielinski, Lozano; Mertens, Milik
Red Bull Salzburg possible starting lineup:
Coronel; Nissen, Ramalho, Wober, Ulmer; Junuzovic, Szoboszlai; Daka, Minamino, Hwang; Haaland
We say: Napoli 4-2 Red Bull Salzburg
Goals are almost a guarantee in this one and despite Napoli's indifferent form of late, their impressive home record and attacking quality is likely to help them secure a third win in four group games.