The on-loan Arsenal striker finally broke Plymouth's brave resistance when he got behind their defence to set up Morten Bisgaard for only his second goal of the season.
The late winner was harsh on Plymouth, who were solid and well organised but lacked the sort of quality that Lupoli was able to provide for Derby.
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Although the incessant rain was a factor, some of the football was below the standard expected in the Championship and there was little goalmouth incident in a sterile first half.
David Norris fired wide in the eighth minute, but Plymouth were forced to make an early change when Sylvan Ebanks-Blake went off with an ankle injury to be replaced by Cherno Samba.
The substitute came close to scoring in the 26th minute when Darren Moore completely missed his kick, but Stephen Bywater tipped the striker's header over the bar.
There was no better a start to the second half with Derby losing on-loan Manchester United midfielder David Jones with a groin strain.
Bisgaard suggested there was more to come from the home side in the 49th minute when he cleverly fashioned an opening for himself on the right and his low shot was well turned away by Romain Larrieu.
From the resulting corner the ball fell invitingly to Moore 15 yards out and his well struck shot was headed clear by Hasney Aljofree positioned by the left-hand post.
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The introduction of Lupoli in the 62nd minute always threatened to give Derby the edge, but the match was beginning to drift towards stalemate until the young Italian finally unlocked Plymouth's stubborn back-line.
Jon Stead picked up the ball near the left-hand touchline and immediately released Lupoli, who darted behind Paul Connolly and delivered a precise pass which Bisgaard slipped into the net from eight yards.
That was cruel on the visitors who had little time in which to respond and although they made two late substitutions, Derby never looked like letting the lead slip away.