Shelvey aggravated his hamstring problem during Sunday's 4-3 defeat against his former club Liverpool in the Premier League and will not feature at the San Paolo stadium.
He joins Michu on the sidelines, with the Spanish forward recovering from ankle surgery.
Pepe Reina is expected to start in goal for Napoli after Rafael sustained a knee injury in last week's goalless first leg in south Wales.
Swansea midfielder Pablo Hernandez believes his team can spring a surprise by beating Napoli.
He said: "Napoli are favourites. They play at home, we don't have an advantage heading into the game. We were better in the first leg but they are favourites.
"Napoli have played in the Champions League this season, they are a big team but we have a chance. I think we can win this game.
"The team has come here with confidence.
"We haven't won our recent games but from our confidence standpoint, those performances were good for us.
"We had a good game in Swansea against Napoli. We played well, controlled possession and we had our chances. But in football, if you don't score you can't win.
"It's a historic game for the club. It's always special to play in Europe. This game is for the players, the club and our fans to enjoy.
"We have to enjoy this moment because to play against a big team in Europe doesn't happen often.
"I've played a lot of games in Europe against big teams. I've played in the Champions League two years but for me the game against Napoli is a special game.
"I think I can make a contribution and help the team win."