All-rounder Afridi hit seven sixes and 10 fours to power Hampshire to 249 for eight, their highest T20 score.
Write off Pakistan at your own peril: Afridi
Skipper James Vince made 55 from 36 balls as Hampshire passed their previous best of 225 for two against Middlesex in 2006 and, faced with an improbable target of 250, the Falcons crumbled to 148 all out with Liam Dawson and Kyle Abbott each taking three wickets.
Hampshire promoted Afridi to opener against the county he played for in 2003 and he swept and drove four boundaries from Wayne Madsen's first over before Calvin Dickinson took two fours from Hardus Viljoen.
Afridi foundation, KMC sign MoU
Afridi's previous high score in the competition this season was 18 but he pulled Ben Cotton for six before driving him over the top of the three-storey media centre.
He reached his fifty off only 20 balls with a top-edged six but after driving Imran Tahir for another huge six, he was dropped on 65 at long-on by Madsen.
It proved expensive as Afridi dispatched Matt Critchley and Tahir for two more sixes on his way to a blistering hundred before he top-edged another big pull and was caught at long-leg.
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