Matthews, who led Melbourne Renegades to victory over Brisbane Heat in last December's WBBL final where she was named player of the match, took three for 32 as England were restricted to 5-144.
She then cracked 71 from 54 balls as the tourists looked to salvage some pride in the series on Monday.
Yet it was not enough as England, for whom Heather Knight earlier top-scored with an unbeaten 66, limited the West Indies to 8-127 to secure a 17-run victory.
Matthews put England in to bat after winning the toss and was rewarded with a disciplined display from her attack.
Zaida James removed Danni Wyatt-Hodge with the first ball of the match - her second successive golden duck - and Sophia Dunkley also fell cheaply.
New captain Nat Sciver-Brunt (37) and Knight repaired the innings before Amy Jones added a useful 22.
Knight occupied 47 balls, hitting seven fours and a six in what was her eighth T20 international half-century, although it did come at the cost of a hamstring injury.
The West Indies also lost a wicket first ball as Lauren Bell bowled Qiana Joseph but Matthews ensured their reply built momentum.
She lacked significant support with Realeanna Grimmond (15) remarkably dropped off three successive balls before holing out to Wyatt-Hodge off the bowling of Charlie Dean.
A rain interruption also broke Matthews' flow and the visitors' hopes effectively ended when the skipper became the sixth wicket to fall when she was caught on the boundary by Em Arlott off Bell.
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