MacLeod's second Twenty20 hundred, with 13 fours and four sixes, saw Derbyshire rack up 211 for two - their joint-second highest total in this format.
That was defended very easily after Lockie Ferguson removed Ben Duckett and Richard Levi in the powerplay, with Northants dismissed for 180 in reply.
MacLeod began by driving Rory Kleinveldt past cover point and then over backward point, before cutting and sweeping Josh Cobb for further boundaries.
A viscous lofted cover-drive was parried for six by a diving Ben Sanderson before a steer past short-third man brought him four more en route to fifty in 33 balls.
His hitting set a good platform at 136 for one after 14 overs and MacLeod then heaved Brett Hutton over extra-cover for six, turned a high full-toss over long-leg for another maximum and slammed his 10th four past mid-off as 22 came from the over.
Luke Procter was slapped wide of mid-on before a drive past point brought up MacLeod's century - just the third for Derbyshire in T20s after Greg Smith and Wes Durston. He finally fell for a career-best equalling 104, miscuing a drive to extra-cover.
MacLeod shared a stand of 126 with Wayne Madsen - a record second-wicket stand for anyone against Northants.
Madsen, as ever, played a clever innings with excellent running between the wickets. He reverse-swept Seekkuge Prasanna for his first boundary and twice steered fours past point before heaving Procter onto the pavilion balcony.
A slower ball from Kleinveldt was driven past extra-cover and he reached a half-century in 32 balls in the final over that yielded 16.
Derbyshire, having been sent in, scored 75 runs in the final six overs. But in the first six, they were given a bright start from Billy Godleman, playing his first T20 this season.
He skipped down to the first ball of the innings to lift Sanderson for four before hoisting Hutton for six over long-on. He pulled Kleinveldt for two fours but having got to 29, drove Procter to deep cover.
The Northants chase never got into gear. Ferguson, introduced in the third over, produced a spell to put the game beyond doubt.
He removed Duckett first ball with one that nipped away, took the edge and was wonderfully held down low at first slip by MacLeod, before a spearing yorker cannoned Levi's off stump.
Kyle Coetzer, playing his first match for Northants since 2015, went to uppercut Hardus Viljoen and was caught at short-third man for a fourth-ball duck as the powerplay ended at 48 for three.
Cobb was then caught at extra-cover trying to drive Alex Hughes' first delivery and the same bowler got a slower ball through Alex Wakely to bowl him for 10. Hughes finished with four for 42 - his final over being struck for 22.
It was part of a brief flurry from Kleinveldt, who blasted four sixes in his 36 from 14 deliveries. The South African and Prasanna, with a 14-ball 29, kept the home support entertained but the lower order were left with far too much to do.
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