Jonathan Tuffey saved a Giampaolo Pazzini penalty but Sergio Pellissier added the third 18 minutes from time.
However, the Northern Ireland keeper tipped Pazzini's spot-kick on to the post and the ball was cleared.
Daniele Mannini grabbed a brace and Giampaolo Pazzini and Reto Ziegler scored the others in Samp's win.
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The Italians were threatening to run riot when they won a penalty after Tuffey had brought down Pazzini.
Meanwhile in Serie A, Giampaolo Pazzini scored twice as AC Milan overran 10-man Lazio 3-0 at the San Siro on Saturday.
Balotelli will be suspended now against Napoli and Giampaolo Pazzini will play.
Galatasaray's Morgan De Sanctis will probably get the nod in goal and Catania's Giuseppe Mascara could join Giuseppe Rossi and Giampaolo Pazzini in attack.
Pazzini has been struggling with injury since the March 8 win over Genoa, but came off the bench late in the game against Fiorentina.
Meanwhile, ahead of the new season a major transfer switch was completed Wednesday with AC Milan and Inter agreeing to swap strikers Giampaolo Pazzini and Antonio Cassano.
Elsewhere, AC Milan claimed a 2-1 win over Siena thanks to goals from Bojan and Giampaolo Pazzini, while there were also wins for Chievo, Genoa and Parma.
Pazzini, who is deputizing for the injured Mario Balotelli, scored his second of the night on the hour mark to put the game beyond the reach of the visitors.
After Iaquinta wasted a defence-splitting De Rossi pass in the 60th minute, Lippi again made a further change with in-form Sampdoria striker Giampaolo Pazzini replacing the ineffective Claudio Marchisio.
With 10 minutes remaining Pazzini was replaced by Christian Vieri and his first taste of the action was to fire in a free-kick from 25 yards that was deflected over.
The struggling visitors took a seventh-minute lead through Sergio Floccari but goals later in the first half from Stefano Guberti and Giampaolo Pazzini were enough to give Samp the three points.
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Indeed, Milan has had a whole range of players stepping up in turn, like centerforward Giampaolo Pazzini, who earlier this season went 11 games without scoring, but on Saturday notched two of the three goals that sank Lazio, allowing Milan to leapfrog its opponent into third place.
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