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The Italian 19-year-old, on loan from Arsenal until the end of the season, struck either side of a Michael Johnson header as the Rams eased to a comfortable victory.
It could all have been different had Southend skipper Kevin Maher put the Shrimpers ahead with the game's first real chance on 21 minutes.
Freddy Eastwood, a £1million target for Derby earlier in the season, chased a long clearance out of his own defence and sent over a pinpoint cross for Maher to aim a low volley towards the bottom corner.
But Lee Grant dived to his right to push the ball around the post for a corner.
Billy Davies' men responded well and, ten minutes later, Lupoli broke down the left and crossed for Steve Howard to volley over from six yards.
Adam Bolder then had a close-range drive kept out by Darryl Flahavan, before Lupoli got his and Derby's first of the afternoon on 40 minutes.
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And just three minutes into the second half County doubled their lead through Johnson. The veteran defender was left completely unmarked at the back post as he headed Matt Oakley's free-kick from the right past the helpless Flahavan.
It was difficult to see a way back for Steve Tilson's men after Johnson's strike, but Eastwood almost halved the deficit when he stretched to volley Simon Francis' cross into the side-netting.
However, it was game over on 64 minutes when Morten Bisgaard slipped a ball through for Lupoli to run on to and beat Flahavan with a cool finish.
And, as if to prove it wasn't to be Southend's day, there was still time for Grant to pull off a miraculous save from Michael Ricketts' point-blank header.
The result lifts Derby up to ninth place in the Championship but Southend drop one to 22nd.