Ivo Pulga guided Cagliari to a fourth consecutive Serie A victory at the expense of bottom side Siena, who had Luis Neto sent off.
Nene had Serse Cosmi's Bianconeri on the back foot with a swift brace in the first half, Marco Sau extending Cagliari's advantage before Erjon Bogdani hit back before the break.
But there was no way back for Siena when Neto saw red deep into the second half, allowing Thiago Ribeiro to make the points safe, only for Emanuele Calaio to grab a late consolation.
Following a dismal start to the season, Cagliari have now moved into eighth place under the stewardship of Pulga, who replaced Massimo Ficcadenti earlier this month.
It took just six minutes for the Rossoblu to take the lead, Nene controlling Daniele Conti's corner before dispatching the ball beyond Gianluca Pegolo.
The Isolani had not scored more than once in any game this season, but Nene nixed that record with the cleanest of direct free-kicks in the 26th minute.
And Sau would give Cagliari their first three-goal haul since April with a quickfire goal just two minutes later.
Scorer turned provider as Nene set his team-mate free behind the Siena defence, Sau dutifully beating Pegolo with a deft touch when one-on-one.
When Davide Astori was penalised for fouling Simone Vergassola in the Cagliari box, the Robur thought they had a lifeline, but Michael Agazzi guessed right to repel Calaio's spotkick.
The visitors would reduce the deficit before the break, though, Bogdani linking up well with Calaio to slip the ball beyond Agazzi in the 42nd minute.
A quieter second period started with an audacious effort from Nene, with Radja Nainggolan trying his luck against Pegolo.
The task was beyond Siena from the 76th minute, though, as Neto received his marching orders for picking up a second yellow card.
Ribeiro was not impressed when Pegolo pushed away his snapshot on the counter, but the Brazilian tucked away his second effort to put the result out of reach.
There was still time, however, for Calaio to make amends for his penalty miss as he tucked away Francesco Valiani's cross in stoppage time.