South Africa were put into bat at the Ageas Bowl on Sunday and scored 5 for 191 off their 20 overs to set England an imposing target and then skittled out the home team for a one-sided victory.
Shamsi's wrist spin accounted for Liam Livingstone, Sam Curran and David Willey, who was bowled first ball to set up a hat-trick chance that Chris Jordan denied him.
But Shamsi had Jordan trapped leg before wicket in his last over, and then Adil Rashid caught out on the boundary, to finish with 5-24 off four overs.
England quickly fell behind the required run rate as none of their batsmen managed to show any of the power hitting from earlier in the limited overs series between the two countries.
They all struggled to deal with the variety of bowling options South Africa subjected them to.
Jonny Bairstow finished their top scorer with 27 runs after coming in at number four, and he was the last man out after watching a procession of batsmen fall around him.
Willey bowled South Africa's opener Quinton de Kock in a wicket maiden opening over at the start of the contest but the tourists went onto set a substantial target as Reeza Hendricks and Aiden Markram both scored half centuries.
Their 87-run partnership also proved decisive after Rilee Rossouw was out for 31 off 18 balls.
Hendricks scored 70 before skying the ball to wicketkeeper Jos Buttler off Jordan while Markram was 51 not out.
There was also a lightening contribution of 22 runs off nine balls from free-swinging captain David Miller, celebrating his 100th T20 appearance for South Africa. It included the only six of his team's innings.
England won the opening match of the T20 series by 41 runs before South Africa bounced back with a 58-run victory to take the series into Sunday's decider.Â
