Pandev struck in the 14th and 25th minutes and gave his side a one-point lead over second-placed AS Roma who host Bologna on Sunday.
Milan rose to ninth spot on eight points after Valter Birsa's powerful long-range drive in the 46th minute secured their second league win of the season.
Pandev's match-winning display for Napoli came after he was played behind the centre forward, the position he had been asking Benitez to put him.
"I said to him that he has no excuses, he was playing in the centre and he had to score goals, and he did," said Benitez.
The Spaniard was criticised in midweek when he rotated his team and they could only muster a 1-1 home draw in the league against lowly Sassuolo.
"We really wanted three points after the horrible night on Wednesday but those nights can happen to anyone," said Macedonian Pandev. "Tonight we played really well and deserved the win."
Massimiliano Allegri's Milan were missing a raft of players including the suspended Mario Balotelli and, apart from a brief period after the goal, they were largely uninspiring.
Three minutes after they took the lead Robinho wasted Andrea Poli's perfect pass by shooting straight at Sampdoria goalkeeper Angelo Da Costa in front of an open goal.
Delio Rossi's struggling Sampdoria offered little of the fighting spirit that helped them score late twice in last week's 2-2 draw at Cagliari and they are third from bottom on two points.
Pandev fluffed one chance for Napoli on the break before breaking through, pouncing on an errant pass from Genoa midfielder Juraj Kucka and skipping past Alessandro Gamberini to calmly shoot his team in front.
He then played a neat one-two with Lorenzo Insigne before finishing well with his right foot from a tight angle.
Genoa, who are 15th in the table, put the visitors under a lot of pressure after Napoli's injured defender Raul Albiol gave way to Paolo Cannavaro at halftime.
That will be a worry for Benitez as he looks to go top of Champions League Group F with a win at Arsenal in midweek.
On Sunday, third-placed Inter Milan travel to Cagliari in Serie A while Juventus, in fourth, visit Torino. Fifth-placed Fiorentina host Parma on Monday.