While the Scudetto holders were held by lowly Frosinone last weekend, a painful loss in Lecce leaves their hosts in serious danger of relegation.
Match preview
Needing points to stay in touch with Italy's top six, Napoli were ultimately forced to settle for a 2-2 draw at Stadio Maradona last Sunday, after they twice let leads slip at home to a side struggling to stay afloat in Serie A.
To make matters worse for the Partenopei, their on-loan striker Walid Cheddira did the damage by scoring both of Frosinone's goals, cancelling out finishes from Victor Osimhen and Matteo Politano.
Following their latest setback, Francesco Calzona's side have now conceded at least twice in each of their last three matches, but at least a lean spell in front of goal has reached its end before European qualification drifted beyond reach.
Since Calzona returned to the club in mid-February, Osimhen and his sidekick Khvicha Kvaratskhelia have been directly involved in the most Serie A strikes - both registering seven goals or assists during that time.
However, the reigning champions - soon to be deposed by Inter Milan, barring a dramatic turn of events - only occupy seventh spot in the standings and trail sixth-placed Atalanta BC by two points, having played one game more.
A top-seven finish may yet prove enough to qualify for Europe, but Lazio, Torino and Fiorentina are all in contention too, so Napoli will be keen to build on a four-match unbeaten streak away from home by securing maximum points at Stadio Castellani.
Including their shock 1-0 success in Naples last November, in which Viktor Kovalenko snatched victory with a stoppage-time winner, Empoli have won four of their last six league meetings with Napoli.
The Tuscan club are in need of a repeat performance this weekend, though, as they sit 17th in the top-flight table with just six rounds remaining and are fighting for survival.
Only one point above 18th-placed Frosinone in a seven-team scrap to avoid filling two more relegation places alongside doomed Salernitana, Empoli were beaten by a late strike at Lecce's Via del Mare last time out.
They have now lost five of their last six fixtures to nil, and since March began they have failed to find the net more often than any other Serie A side, also losing the most matches.
Now, head coach Davide Nicola - a renowned survival expert - will aim to defy the odds and lead his team to successive home wins for the first time since last May, when a run of three in a row dragged them definitively clear of danger.
Empoli Serie A form:
L
L
L
L
W
L
Napoli Serie A form:
W
D
D
L
W
D
Napoli form (all competitions):
D
L
D
L
W
D
Team News
Francesco Calzona must make at least two changes to Napoli's leaky defence on Saturday, as both Amir Rrahmani and Mario Rui will serve one-match bans, with the latter having been dismissed deep into stoppage time against Frosinone.
Juan Jesus should overcome a back problem to replace Rrahmani in the centre, but the absence of injured left-back Mathias Olivera could require some improvisation; Pasquale Mazzocchi may be asked to play on his less-favoured side.
Cyril Ngonge returns from suspension and is set to start on the bench, as Victor Osimhen, Khvicha Kvaratskhelia and Matteo Politano continue to join forces up front.
In midfield, Piotr Zielinski - who is expected to leave Naples when his contract expires this summer - returns to a club he played 63 Serie A matches for, scoring five goals in the process; since then, he has scored twice against Empoli in the league.
The hosts, meanwhile, will be without Ghanaian winger Emmanuel Gyasi, who is suspended due to yellow-card accumulation.
Tyronne Ebuehi is ruled out for the rest of the season, but Ardian Ismajli may be able to play a part this weekend, having recently been sidelined by a thigh injury.
There is plenty of competition for places up front, as Alberto Cerri led Empoli's attack last week, but Stiven Shpendi, M'Baye Niang, Francesco Caputo and Mattia Destro are all available too.
Empoli possible starting lineup:
Caprile; Bereszynski, Walukiewicz, Luperto; Cancellieri, Marin, Maleh, Pezzella; Zurkowski, Cambiaghi; Niang
Napoli possible starting lineup:
Meret; Di Lorenzo, Jesus, Ostigard, Mazzocchi; Anguissa, Lobotka, Zielinski; Politano, Osimhen, Kvaratskhelia